Aminopiperidines as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes

ABSTRACT

The present invention is directed to novel substituted aminopiperidines which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DPP-IV inhibitors”) and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No.PCT/US2005/034775, filed 27 Sep. 2005, which claims the benefit under 35U.S.C. 119(e) of U.S. Provisional Application No. 60/615,478, filed 1Oct. 2004.

FIELD OF THE INVENTION

The present invention relates to novel substituted aminopiperidineswhich are inhibitors of the dipeptidyl peptidase-IV enzyme (“DPP-IVinhibitors”) and which are useful in the treatment or prevention ofdiseases in which the dipeptidyl peptidase-IV enzyme is involved, suchas diabetes and particularly Type 2 diabetes. The invention is alsodirected to pharmaceutical compositions comprising these compounds andthe use of these compounds and compositions in the prevention ortreatment of such diseases in which the dipeptidyl peptidase-IV enzymeis involved.

BACKGROUND OF THE INVENTION

Diabetes refers to a disease process derived from multiple causativefactors and characterized by elevated levels of plasma glucose orhyperglycemia in the fasting state or after administration of glucoseduring an oral glucose tolerance test. Persistent or uncontrolledhyperglycemia is associated with increased and premature morbidity andmortality. Often abnormal glucose homeostasis is associated bothdirectly and indirectly with alterations of the lipid, lipoprotein andapolipoprotein metabolism and other metabolic and hemodynamic disease.Therefore patients with Type 2 diabetes mellitus are at especiallyincreased risk of macrovascular and microvascular complications,including coronary heart disease, stroke, peripheral vascular disease,hypertension, nephropathy, neuropathy, and retinopathy. Therefore,therapeutical control of glucose homeostasis, lipid metabolism andhypertension are critically important in the clinical management andtreatment of diabetes mellitus.

There are two generally recognized forms of diabetes. In type 1diabetes, or insulin-dependent diabetes mellitus (IDDM), patientsproduce little or no insulin, the hormone which regulates glucoseutilization. In Type 2 diabetes, or noninsulin dependent diabetesmellitus (NIDDM), patients often have plasma insulin levels that are thesame or even elevated compared to nondiabetic subjects; however, thesepatients have developed a resistance to the insulin stimulating effecton glucose and lipid metabolism in the main insulin-sensitive tissues,which are muscle, liver and adipose tissues, and the plasma insulinlevels, while elevated, are insufficient to overcome the pronouncedinsulin resistance.

Insulin resistance is not primarily due to a diminished number ofinsulin receptors but to a post-insulin receptor binding defect that isnot yet understood. This resistance to insulin responsiveness results ininsufficient insulin activation of glucose uptake, oxidation and storagein muscle and inadequate insulin repression of lipolysis in adiposetissue and of glucose production and secretion in the liver.

The available treatments for Type 2 diabetes, which have not changedsubstantially in many years, have recognized limitations. While physicalexercise and reductions in dietary intake of calories will dramaticallyimprove the diabetic condition, compliance with this treatment is verypoor because of well-entrenched sedentary lifestyles and excess foodconsumption, especially of foods containing high amounts of saturatedfat. Increasing the plasma level of insulin by administration ofsulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, whichstimulate the pancreatic β-cells to secrete more insulin, and/or byinjection of insulin when sulfonylureas or meglitinide becomeineffective, can result in insulin concentrations high enough tostimulate the very insulin-resistant tissues. However, dangerously lowlevels of plasma glucose can result from administration of insulin orinsulin secretagogues (sulfonylureas or meglitinide), and an increasedlevel of insulin resistance due to the even higher plasma insulin levelscan occur. The biguanides increase insulin sensitivity resulting in somecorrection of hyperglycemia. However, the two biguanides, phenformin andmetformin, can induce lactic acidosis and nausea/diarrhea. Metformin hasfewer side effects than phenformin and is often prescribed for thetreatment of Type 2 diabetes.

The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a morerecently described class of compounds with potential for amelioratingmany symptoms of Type 2 diabetes. These agents substantially increaseinsulin sensitivity in muscle, liver and adipose tissue in severalanimal models of Type 2 diabetes resulting in partial or completecorrection of the elevated plasma levels of glucose without occurrenceof hypoglycemia. The glitazones that are currently marketed are agonistsof the peroxisome proliferator activated receptor (PPAR), primarily thePPAR-gamma subtype. PPAR-gamma agonism is generally believed to beresponsible for the improved insulin sensitization that is observed withthe glitazones. Newer PPAR agonists that are being tested for treatmentof Type 2 diabetes are agonists of the alpha, gamma or delta subtype, ora combination of these, and in many cases are chemically different fromthe glitazones (i.e., they are not thiazolidinediones). Serious sideeffects (e.g. liver toxicity) have occurred with some of the glitazones,such as troglitazone.

Additional methods of treating the disease are still underinvestigation. New biochemical approaches that have been recentlyintroduced or are still under development include treatment withalpha-glucosidase inhibitors (e.g. acarbose) and protein tyrosinephosphatase-1B (PTP-1B) inhibitors.

Compounds that are inhibitors of the dipeptidyl peptidase-IV (“DPP-IV”)enzyme are under investigation as drugs that may be useful in thetreatment of diabetes, and particularly Type 2 diabetes. See, forexample, international patent publications WO 97/40832; WO 98/19998; WO01/68603; WO 02/38541; WO 02/076450; WO 03/000180; WO 03/000181; WO03/024942; WO 03/033524; WO 03/035057; WO 03/035067; WO 03/037327; WO03/074500; WO 03/082817; WO 04/007468; WO 04/018467; WO 04/026822; WO04/032836; WO 04/037181; WO 04/041795; WO 04/043940; WO 04/046106; WO04/050022; WO 04/058266; WO 04/064778; WO 04/069162; WO 04/071454; U.S.Pat. Nos. 5,939,560; 6,011,155; 6,107,317; 6,110,949; 6,166,063;6,124,305; 6,303,661; 6,432,969; 6,617,340; and 6,699,871; Bioorg. Med.Chem. Lett., 6: 1163-1166 (1996); and Bioorg. Med. Chem. Lett. 6:2745-2748 (1996); for a description of different structural classes ofDPP-IV inhibitors. The usefulness of DPP-IV inhibitors in the treatmentof Type 2 diabetes is based on the fact that DPP-IV in vivo readilyinactivates glucagon like peptide-1 (GLP-1) and gastric inhibitorypeptide (GIP). GLP-1 and GIP are incretins and are produced when food isconsumed. The incretins stimulate production of insulin. Inhibition ofDPP-IV leads to decreased inactivation of the incretins, and this inturn results in increased effectiveness of the incretins in stimulatingproduction of insulin by the pancreas. DPP-IV inhibition thereforeresults in an increased level of serum insulin. Advantageously, sincethe incretins are produced by the body only when food is consumed,DPP-IV inhibition is not expected to increase the level of insulin atinappropriate times, such as between meals, which can lead toexcessively low blood sugar (hypoglycemia). Inhibition of DPP-IV istherefore expected to increase insulin without increasing the risk ofhypoglycemia, which is a dangerous side effect associated with the useof insulin secretagogues.

DPP-IV inhibitors also have other therapeutic utilities, as discussedherein. DPP-IV inhibitors have not been studied extensively forutilities other than diabetes. New compounds are needed so that improvedDPP-IV inhibitors can be found for the treatment of diabetes andpotentially other diseases and conditions. The therapeutic potential ofDPP-IV inhibitors for the treatment of Type 2 diabetes is discussed byD. J. Drucker in Exp. Opin. Invest. Drugs, 12: 87-100 (2003); by K.Augustyns, et al., in Exp. Opin. Ther. Patents, 13: 499-510 (2003); andby C. F. Deacon, et al., in Exp. Opin. Investig. Drugs, 13: 1091-1102(2004).

SUMMARY OF THE INVENTION

The present invention is directed to novel substituted aminopiperidineswhich are inhibitors of the dipeptidyl peptidase-IV enzyme (“DPP-IVinhibitors”) and which are useful in the treatment or prevention ofdiseases in which the dipeptidyl peptidase-IV enzyme is involved, suchas diabetes and particularly Type 2 diabetes. The invention is alsodirected to pharmaceutical compositions comprising these compounds andthe use of these compounds and compositions in the prevention ortreatment of such diseases in which the dipeptidyl peptidase-IV enzymeis involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to substituted aminopiperidines that areuseful as inhibitors of dipeptidyl peptidase-IV. Compounds of thepresent invention are described by structural formula I:

and pharmaceutically acceptable salts thereof; whereineach n is independently 0, 1, 2 or 3;Ar is phenyl unsubstituted or substituted with one to five R³substituents;each R³ is independently selected from the group consisting of

-   -   halogen,    -   cyano,    -   hydroxy,    -   C₁₋₆ alkyl, unsubstituted or substituted with one to five        halogens, and    -   C₁₋₆ alkoxy, unsubstituted or substituted with one to five        halogens;        R¹ is heteroaryl unsubstituted or substituted with one to four        R² substituents;        each R² is independently selected from the group consisting of    -   hydroxy,    -   halogen,    -   cyano,    -   nitro,    -   C₁₋₁₀ alkoxy, wherein alkoxy is unsubstituted or substituted        with one to five substituents independently selected from        halogen or hydroxy,    -   C₁₋₁₀ alkyl, wherein alkyl is unsubstituted or substituted with        one to five substituents independently selected from halogen or        hydroxy,    -   C₂₋₁₀ alkenyl, wherein alkenyl is unsubstituted or substituted        with one to five substituents independently selected from        halogen or hydroxy,    -   (CH₂)_(n)-aryl, wherein aryl is unsubstituted or substituted        with one to five substituents independently selected hydroxy,        halogen, cyano, nitro, CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkyl,        and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted or        substituted with one to five halogens,    -   (CH₂)_(n)-heteroaryl, wherein heteroaryl is unsubstituted or        substituted with one to three substituents independently        selected from hydroxy, halogen, cyano, nitro, CO₂H, C₁₋₆        alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and        alkoxy are unsubstituted or substituted with one to five        halogens,    -   (CH₂)_(n)-heterocyclyl, wherein heterocyclyl is unsubstituted or        substituted with one to three substituents independently        selected from oxo, hydroxy, halogen, cyano, nitro, CO₂H, C₁₋₆        alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and        alkoxy are unsubstituted or substituted with one to five        halogens,    -   (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is unsubstituted        or substituted with one to three substituents independently        selected from halogen, hydroxy, cyano, nitro, CO₂H, C₁₋₆        alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and        alkoxy are unsubstituted or substituted with one to five        halogens,    -   (CH₂)_(n)—COOH,    -   (CH₂)_(n)—COOC₁₋₆ alkyl,    -   (CH₂)_(n)—NR⁴R⁵,    -   (CH₂)_(n)—CONR⁴R⁵,    -   (CH₂)_(n)—OCONR⁴R⁵,    -   (CH₂)_(n)—SO₂NR⁴R⁵,    -   (CH₂)_(n)—SO₂R⁶,    -   (CH₂)_(n)—NR⁷SO₂R⁶,    -   (CH₂)_(n)—NR⁷CONR⁴R⁵,    -   (CH₂)_(n)—NR⁷COR⁷, and    -   (CH₂)_(n)—NR⁷CO₂R⁶;        wherein any individual methylene (CH₂) carbon atom in (CH₂)_(n)        is unsubstituted or substituted with one to two groups        independently selected from halogen, hydroxy, C₁₋₄ alkyl, and        C₁₋₄ alkoxy, wherein alkyl and alkoxy are unsubstituted or        substituted with one to five halogens;        R⁴ and R⁵ are each independently selected from the group        consisting of    -   hydrogen,    -   (CH₂)_(n)-phenyl,    -   (CH₂)_(n)—C₃₋₆ cycloalkyl, and    -   C₁₋₆ alkyl;        wherein alkyl is unsubstituted or substituted with one to five        substituents independently selected from halogen and hydroxy and        wherein phenyl and cycloalkyl are unsubstituted or substituted        with one to five substituents independently selected from        halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and        alkoxy are unsubstituted or substituted with one to five        halogens;

-   or R⁴ and R⁵ substituents together with the nitrogen atom to which    they are attached form a heterocyclic ring selected from azetidine,    pyrrolidine, piperidine, piperazine, and morpholine wherein said    heterocyclic ring is unsubstituted or substituted with one to three    substituents independently selected from halogen, hydroxy, C₁₋₆    alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted    or substituted with one to five halogens;    each R⁶ is independently C₁₋₆ alkyl, wherein alkyl is unsubstituted    or substituted with one to five substituents independently selected    from halogen and hydroxyl; and    R⁷ is hydrogen or R⁶.

In one embodiment of the compounds of the present invention, R³ isselected from the group consisting of fluorine, chlorine, bromine,methyl, trifluoromethyl, and trifluoromethoxy. In a class of thisembodiment, R³ is fluorine, chlorine, methyl, or trifluoromethyl.

In a second embodiment of the compounds of the present invention, R¹ isa heteroaryl group selected from the group consisting of:

wherein the heteroaryl group is unsubstituted or substituted with one tofour R² substituents.

In a class of this embodiment, R¹ is selected from the group consistingof:

In a subclass of this class, R¹ is selected from the group consistingof:

In a subclass of this subclass, R¹ is selected from the group consistingof:

In a third embodiment of the compounds of the present invention, R² isselected from the group consisting of

-   -   halogen,    -   cyano,    -   nitro,    -   C₁₋₁₀ alkoxy, wherein alkoxy is unsubstituted or substituted        with one to five substituents independently selected from        halogen or hydroxy,    -   C₁₋₁₀ alkyl, wherein alkyl is unsubstituted or substituted with        one to five substituents independently selected from halogen or        hydroxy,    -   aryl, wherein aryl is unsubstituted or substituted with one to        five substituents independently selected hydroxy, halogen,        cyano, nitro, CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆        alkoxy, wherein alkyl and alkoxy are unsubstituted or        substituted with one to five halogens,    -   heteroaryl, wherein heteroaryl is unsubstituted or substituted        with one to three substituents independently selected from        hydroxy, halogen, cyano, nitro, CO₂H, C₁₋₆ alkyloxycarbonyl,        C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are        unsubstituted or substituted with one to five halogens,    -   C₃₋₆ cycloalkyl, wherein cycloalkyl is unsubstituted or        substituted with one to three substituents independently        selected from halogen, hydroxy, cyano, nitro, CO₂H, C₁₋₆        alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and        alkoxy are unsubstituted or substituted with one to five        halogens,    -   COOH, and    -   COOC₁₋₆ alkyl.

In a class of this embodiment, R² is selected from the group consistingof:

fluoro,

chloro,

cyano,

nitro,

C₁₋₄ alkyl,

trifluoromethyl,

methoxy,

4-fluorophenyl,

cyclohexyl,

cyclopropyl,

ethoxycarbonyl,

carboxy,

furyl,

pyridyl, and

thienyl.

In a fourth embodiment of the compounds of the present invention, thereare provided compounds of structural formulae Ia and Ib of the indicatedstereochemical configuration having a trans orientation of the Ar andNH₂ substituents on the two stereogenic piperidine carbon atoms markedwith an *:

wherein Ar and R¹ are as described above.

In a class of this fourth embodiment, there are provided compounds ofstructural formula Ia of the indicated absolute stereochemicalconfiguration having a trans orientation of the Ar and NH₂ substituentson the two stereogenic piperidine carbon atoms marked with an *:

In a subclass of this class, Ar is phenyl unsubstituted or substitutedwith one to three R³ substituents independently selected from fluorine,chlorine, methyl, and trifluoromethyl; and

R¹ is a heteroaryl group selected from the group consisting of:

wherein said heteroaryl group is unsubstituted or substituted with oneto two R² substituents independently selected from the group consistingof:fluoro,chloro,cyano,nitro,C₁₋₄ alkyl,trifluoromethyl,methoxy,4-fluorophenyl,cyclohexyl,cyclopropyl,ethoxycarbonyl,carboxy,furyl,pyridyl, andthienyl.

In a subclass of this subclass, R¹ is selected from the group consistingof:

Nonlimiting examples of compounds of the present invention that areuseful as dipeptidyl peptidase-IV inhibitors are the followingstructures having the indicated absolute stereochemical configurationsat the two stereogenic piperidine carbon atoms:

and pharmaceutically acceptable salts thereof.

As used herein the following definitions are applicable.

“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxyand alkanoyl, means carbon chains which may be linear or branched, andcombinations thereof, unless the carbon chain is defined otherwise.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and thelike.

The term “cycloalkyl” refers to a saturated hydrocarbon containing onering having a specified number of carbon atoms. Examples of cycloalkylinclude cyclopropyl (cPr), cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, and the like. A cycloalkyl group is monocyclicunless stated otherwise. Cycloalkyl groups are saturated unlessotherwise defined.

The term “alkoxy” refers to straight or branched chain alkoxides of thenumber of carbon atoms specified (e.g., C₁₋₁₀ alkoxy), or any numberwithin this range [i.e., methoxy (MeO—), ethoxy, isopropoxy, etc.].

The term “alkylthio” refers to straight or branched chain alkylsulfidesof the number of carbon atoms specified (e.g., C₁₋₁₀ alkylthio), or anynumber within this range [i.e., methylthio (MeS—), ethylthio,isopropylthio, etc.].

The term “alkylamino” refers to straight or branched alkylamines of thenumber of carbon atoms specified (e.g., C₁₋₆ alkylamino), or any numberwithin this range [i.e., methylamino, ethylamino, isopropylamino,t-butylamino, etc.].

The term “alkylsulfonyl” refers to straight or branched chainalkylsulfones of the number of carbon atoms specified (e.g., C₁₋₆alkylsulfonyl), or any number within this range [i.e., methylsulfonyl(MeSO₂—), ethylsulfonyl, isopropylsulfonyl, etc.].

The term “alkyloxycarbonyl” refers to straight or branched chain estersof a carboxylic acid derivative of the present invention of the numberof carbon atoms specified (e.g., C₁₋₆ alkyloxycarbonyl), or any numberwithin this range [i.e., methyloxycarbonyl (MeOCO—), ethyloxycarbonyl,or butyloxycarbonyl].

“Aryl” means a mono- or polycyclic aromatic ring system containingcarbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.The most preferred aryl is phenyl.

The term “heterocyclyl” refers to saturated or unsaturated non-aromaticrings or ring systems containing at least one heteroatom selected fromO, S and N, further including the oxidized forms of sulfur, namely SOand SO₂. Examples of heterocycles include tetrahydrofuran (THF),dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine,piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline,pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane,1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, pyrrolidinone,oxazolidin-2-one, imidazolidine-2-one, pyridone, and the like.

“Heteroaryl” means an aromatic or partially aromatic heterocycle thatcontains at least one ring heteroatom selected from O, S and N.Heteroaryls also include heteroaryls fused to other kinds of rings, suchas aryls, cycloalkyls and heterocycles that are not aromatic. Examplesof heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl,pyrazolyl, pyridinyl, 2-oxo-(1H)-pyridinyl (2-hydroxy-pyridinyl),oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl,pyrimidinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl,indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl,phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl,quinoxalinyl, purinyl, pteridinyl, furazanyl, isobenzylfuranyl,benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl,isoquinolyl, dibenzofuranyl, imidazo[1,2-a]pyridinyl,imidazo[4,5-b]pyridinyl, [1,2,4-triazolo][4,3-a]pyridinyl,pyrazolo[1,5-a]pyridinyl, [1,2,4-triazolo][1,5-a]pyridinyl,2-oxo-1,3-benzoxazolyl, 4-oxo-3H-quinazolinyl,3-oxo-[1,2,4]-triazolo[4,3-a]-2H-pyridinyl,5-oxo-[1,2,4]-4H-oxadiazolyl, 2-oxo-[1,3,4]-3H-oxadiazolyl,2-oxo-1,3-dihydro-2H-imidazolyl, 3-oxo-2,4-dihydro-3H-1,2,4-triazolyl,imidazo[1,2-a]pyrimidinyl, imidazo[1,5-a]pyrimidinyl,imidazo[4,5-b]pyridyl, pyrazolo[1,5-a]pyrimidinyl,[1,2,4-triazolo][1,5-a]pyrimidinyl, [1,2,4-triazolo][4,3-a]pyrimidinyl,[1,2,3-triazolo][1,5-a]pyrimidinyl, pyrazolo[1,5-b]pyridazinyl,imidazo[1,5-b]pyridazinyl, imidazo[1,2-b]pyridazinyl,[1,2,4-triazolo][4,3-b]pyridazinyl, [1,2,4-triazolo][1,5-b]pyridazinyl,pyrido[2,3-b]pyrazinyl, pyrido[3,2-d]pyrimidinyl,pyrido[2,3-b]pyrimidinyl, pyrido[3,2-d]pyrimidin-4(3H)-one,pyrazino[2,3-b]pyrazinyl, 1-oxido-pyrazino[2,3-b]pyrazinyl,[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one,[1,2,4]thiadiazolo[2,3-b]pyridazin-2-one,pyridazino[1,6-a][1,3,5]triazin-4-one,pyridazino[1,6-a][1,3,5]triazin-2-one,3,4-dihydro-2H-pyrimido[1,2-b]pyridazine-2-one,and the like. For heterocyclyl and heteroaryl groups, rings and ringsystems containing from 3-15 atoms are included, forming 1-3 rings.

“Halogen” refers to fluorine, chlorine, bromine and iodine. Chlorine andfluorine are generally preferred. Fluorine is most preferred when thehalogens are substituted on an alkyl or alkoxy group (e.g. CF₃₀ andCF₃CH₂O).

The compounds of the present invention contain one or more asymmetriccenters and can thus occur as racemates, racemic mixtures, singleenantiomers, diastereomeric mixtures, and individual diastereomers. Inparticular the compounds of the present invention have an asymmetriccenter at the stereogenic carbon atoms marked with an * in Formulae Iaand Ib. Additional asymmetric centers may be present depending upon thenature of the various substituents on the molecule. Each such asymmetriccenter will independently produce two optical isomers and it is intendedthat all of the possible optical isomers and diastereomers in mixturesand as pure or partially purified compounds are included within theambit of this invention. The present invention is meant to comprehendall such isomeric forms of these compounds.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist as tautomers, whichhave different points of attachment of hydrogen accompanied by one ormore double bond shifts. For example, a ketone and its enol form areketo-enol tautomers. The individual tautomers as well as mixturesthereof are encompassed with compounds of the present invention.

Formula I shows the structure of the class of compounds withoutpreferred stereochemistry. Formulae Ia and Ib show the preferredstereochemistry at the stereogenic carbon atom to which are attached theAr and NH₂ groups.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the X-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

It will be understood that, as used herein, references to the compoundsof structural formula I are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds ortheir pharmaceutically acceptable salts or in other syntheticmanipulations.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salt” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids including inorganic or organic basesand inorganic or organic acids. Salts of basic compounds encompassedwithin the term “pharmaceutically acceptable salt” refer to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts of basic compounds of the present inventioninclude, but are not limited to, the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, hexylresorcinate, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate),palmitate, pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide and valerate. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof include, but are not limitedto, salts derived from inorganic bases including aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,mangamous, potassium, sodium, zinc, and the like. Particularly preferredare the ammonium, calcium, magnesium, potassium, and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, cyclic amines, andbasic ion-exchange resins, such as arginine, betaine, caffeine, choline,N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,isopropylamine, lysine, methylglucamine, morpholine, piperazine,piperidine, polyamine resins, procaine, purines, theobromine,triethylamine, trimethylamine, tripropylamine, tromethamine, and thelike.

Also, in the case of a carboxylic acid (—COOH) or alcohol group beingpresent in the compounds of the present invention, pharmaceuticallyacceptable esters of carboxylic acid derivatives, such as methyl, ethyl,or pivaloyloxymethyl, or acyl derivatives of alcohols, such as acetateor maleate, can be employed. Included are those esters and acyl groupsknown in the art for modifying the solubility or hydrolysischaracteristics for use as sustained-release or prodrug formulations.

Solvates, and in particular, the hydrates of the compounds of structuralformula I are included in the present invention as well.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein.

The subject compounds are useful in a method of inhibiting thedipeptidyl peptidase-IV enzyme in a patient such as a mammal in need ofsuch inhibition comprising the administration of an effective amount ofthe compound. The present invention is directed to the use of thecompounds disclosed herein as inhibitors of dipeptidyl peptidase-IVenzyme activity.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals including, but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent, such as a mouse, species can be treated.However, the method can also be practiced in other species, such asavian species (e.g., chickens).

The present invention is further directed to a method for themanufacture of a medicament for inhibiting dipeptidyl peptidase-IVenzyme activity in humans and animals comprising combining a compound ofthe present invention with a pharmaceutically acceptable carrier ordiluent. More particularly, the present invention is directed to the useof a compound of structural formula I in the manufacture of a medicamentfor use in treating a condition selected from the group consisting ofhyperglycemia, Type 2 diabetes, obesity, and a lipid disorder in amammal, wherein the lipid disorder is selected from the group consistingof dyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL, and high LDL.

The subject treated in the present methods is generally a mammal,preferably a human being, male or female, in whom inhibition ofdipeptidyl peptidase-IV enzyme activity is desired. The term“therapeutically effective amount” means the amount of the subjectcompound that will elicit the biological or medical response of atissue, system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention asinhibitors of dipeptidyl peptidase-IV enzyme activity may bedemonstrated by methodology known in the art. Inhibition constants aredetermined as follows. A continuous fluorometric assay is employed withthe substrate Gly-Pro-AMC, which is cleaved by DPP-IV to release thefluorescent AMC leaving group. The kinetic parameters that describe thisreaction are as follows: K_(m)=50 μM; k_(cat)=75 s⁻¹;k_(cat)/K_(m)=1.5×10⁶ M⁻¹s⁻¹. A typical reaction contains approximately50 pM enzyme, 50 μM Gly-Pro-AMC, and buffer (100 mM HEPES, pH 7.5, 0.1mg/ml BSA) in a total reaction volume of 100 μl. Liberation of AMC ismonitored continuously in a 96-well plate fluorometer using anexcitation wavelength of 360 nm and an emission wavelength of 460 nm.Under these conditions, approximately 0.8 μM AMC is produced in 30minutes at 25 degrees C. The enzyme used in these studies was soluble(transmembrane domain and cytoplasmic extension excluded) human proteinproduced in a baculovirus expression system (Bac-To-Bac, Gibco BRL). Thekinetic constants for hydrolysis of Gly-Pro-AMC and GLP-1 were found tobe in accord with literature values for the native enzyme. To measurethe dissociation constants for compounds, solutions of inhibitor in DMSOwere added to reactions containing enzyme and substrate (final DMSOconcentration is 1%). All experiments were conducted at room temperatureusing the standard reaction conditions described above. To determine thedissociation constants (K_(i)), reaction rates were fit by non-linearregression to the Michaelis-Menton equation for competitive inhibition.The errors in reproducing the dissociation constants are typically lessthan two-fold.

In particular, the compounds of the following examples had activity ininhibiting the dipeptidyl peptidase-IV enzyme in the aforementionedassays, generally with an IC₅₀ of less than about 1 μM. Such a result isindicative of the intrinsic activity of the compounds in use asinhibitors the dipeptidyl peptidase-IV enzyme activity.

Dipeptidyl peptidase-IV enzyme (DPP-IV) is a cell surface protein thathas been implicated in a wide range of biological functions. It has abroad tissue distribution (intestine, kidney, liver, pancreas, placenta,thymus, spleen, epithelial cells, vascular endothelium, lymphoid andmyeloid cells, serum), and distinct tissue and cell-type expressionlevels. DPP-IV is identical to the T cell activation marker CD26, and itcan cleave a number of immunoregulatory, endocrine, and neurologicalpeptides in vitro. This has suggested a potential role for thispeptidase in a variety of disease processes in humans or other species.

Accordingly, the subject compounds are useful in a method for theprevention or treatment of the following diseases, disorders andconditions.

Type 2 Diabetes and Related Disorders: It is well established that theincretins GLP-1 and GIP are rapidly inactivated in vivo by DPP-IV.Studies with DPP-IV^((−/−))-deficient mice and preliminary clinicaltrials indicate that DPP-IV inhibition increases the steady stateconcentrations of GLP-1 and GIP, resulting in improved glucosetolerance. By analogy to GLP-1 and GIP, it is likely that other glucagonfamily peptides involved in glucose regulation are also inactivated byDPP-IV (eg. PACAP). Inactivation of these peptides by DPP-IV may alsoplay a role in glucose homeostasis. The DPP-IV inhibitors of the presentinvention therefore have utility in the treatment of Type 2 diabetes andin the treatment and prevention of the numerous conditions that oftenaccompany Type 2 diabetes, including Syndrome X (also known as MetabolicSyndrome), reactive hypoglycemia, and diabetic dyslipidemia. Obesity,discussed below, is another condition that is often found with Type 2diabetes that may respond to treatment with the compounds of thisinvention.

The following diseases, disorders and conditions are related to Type 2diabetes, and therefore may be treated, controlled or in some casesprevented, by treatment with the compounds of this invention: (1)hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4)obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) irritable bowel syndrome, (15) inflammatorybowel disease, including Crohn's disease and ulcerative colitis, (16)other inflammatory conditions, (17) pancreatitis, (18) abdominalobesity, (19) neurodegenerative disease, (20) retinopathy, (21)nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarianhyperandrogenism (polycystic ovarian syndrome), and other disorderswhere insulin resistance is a component. In Syndrome X, also known asMetabolic Syndrome, obesity is thought to promote insulin resistance,diabetes, dyslipidemia, hypertension, and increased cardiovascular risk.Therefore, DPP-IV inhibitors may also be useful to treat hypertensionassociated with this condition.

Obesity: DPP-IV inhibitors may be useful for the treatment of obesity.This is based on the observed inhibitory effects on food intake andgastric emptying of GLP-1 and GLP-2. Exogenous administration of GLP-1in humans significantly decreases food intake and slows gastric emptying(Am. J. Physiol., 277: R910-R916 (1999)). ICV administration of GLP-1 inrats and mice also has profound effects on food intake (Nature Medicine,2: 1254-1258 (1996)). This inhibition of feeding is not observed inGLP-1R^((−/−)) mice, indicating that these effects are mediated throughbrain GLP-1 receptors. By analogy to GLP-1, it is likely that GLP-2 isalso regulated by DPP-IV. ICV administration of GLP-2 also inhibits foodintake, analogous to the effects observed with GLP-1 (Nature Medicine,6: 802-807 (2000)). In addition, studies with DPP-IV deficient micesuggest that these animals are resistant to diet-induced obesity andassociated pathology (e.g. hyperinsulinonemia).Cardiovascular Disease: GLP-1 has been shown to be beneficial whenadministered to patients following acute myocardial infarction, leadingto improved left ventricular function and reduced mortality afterprimary angioplasty (Circulation, 109: 962-965 (2004)). GLP-1administration is also useful for the treatment of left ventricularsystolic dysfunction in dogs with dilated cardiomyopathy and ischemicinduced left ventricular dysfunction, and thus may prove useful for thetreatment of patients with heart failure (US2004/0097411). DPP-IVinhibitors are expected to show similar effects through their ability tostabilize endogenous GLP-1.Growth Hormone Deficiency: DPP-IV inhibition may be useful for thetreatment of growth hormone deficiency, based on the hypothesis thatgrowth-hormone releasing factor (GRF), a peptide that stimulates releaseof growth hormone from the anterior pituitary, is cleaved by the DPP-IVenzyme in vivo (WO 00/56297). The following data provide evidence thatGRF is an endogenous substrate: (1) GRF is efficiently cleaved in vitroto generate the inactive product GRF[3-44] (BBA 1122: 147-153 (1992));(2) GRF is rapidly degraded in plasma to GRF[344]; this is prevented bythe DPP-IV inhibitor diprotin A; and (3) GRF[3-44] is found in theplasma of a human GRF transgenic pig (J. Clin. Invest., 83: 1533-1540(1989)). Thus DPP-IV inhibitors may be useful for the same spectrum ofindications which have been considered for growth hormone secretagogues.Intestinal Injury: The potential for using DPP-IV inhibitors for thetreatment of intestinal injury is suggested by the results of studiesindicating that glucagon-like peptide-2 (GLP-2), a likely endogenoussubstrate for DPP-IV, may exhibit trophic effects on the intestinalepithelium (Regulatory Peptides 90: 27-32 (2000)). Administration ofGLP-2 results in increased small bowel mass in rodents and attenuatesintestinal injury in rodent models of colitis and enteritis.Immunosuppression: DPP-IV inhibition may be useful for modulation of theimmune response, based upon studies implicating the DPP-IV enzyme in Tcell activation and in chemokine processing, and efficacy of DPP-IVinhibitors in in vivo models of disease. DPP-IV has been shown to beidentical to CD26, a cell surface marker for activated immune cells. Theexpression of CD26 is regulated by the differentiation and activationstatus of immune cells. It is generally accepted that CD26 functions asa co-stimulatory molecule in in vitro models of T cell activation. Anumber of chemokines contain proline in the penultimate position,presumably to protect them from degradation by non-specificaminopeptidases. Many of these have been shown to be processed in vitroby DPP-IV. In several cases (RANTES, LD78-beta, MDC, eotaxin,SDF-1alpha), cleavage results in an altered activity in chemotaxis andsignaling assays. Receptor selectivity also appears to be modified insome cases (RANTES). Multiple N-terminally truncated forms of a numberof chemokines have been identified in in vitro cell culture systems,including the predicted products of DPP-IV hydrolysis.

DPP-IV inhibitors have been shown to be efficacious immunosuppressantsin animal models of transplantation and arthritis. Prodipine(Pro-Pro-diphenyl-phosphonate), an irreversible inhibitor of DPP-IV, wasshown to double cardiac allograft survival in rats from day 7 to day 14(Transplantation, 63: 1495-1500 (1997)). DPP-IV inhibitors have beentested in collagen and alkyldiamine-induced arthritis in rats and showeda statistically significant attenuation of hind paw swelling in thismodel [Int. J. Immunopharmacology. 19:15-24 (1997) andImmunopharmacology, 40: 21-26 (1998)]. DPP-IV is upregulated in a numberof autoimmune diseases including rheumatoid arthritis, multiplesclerosis, Graves' disease, and Hashimoto's thyroiditis (ImmunologyToday 20: 367-375 (1999)).

HIV Infection: DPP-IV inhibition may be useful for the treatment orprevention of HIV infection or AIDS because a number of chemokines whichinhibit HIV cell entry are potential substrates for DPP-IV (ImmunologyToday. 20: 367-375 (1999)). In the case of SDF-1alpha, cleavagedecreases antiviral activity (PNAS, 95: 6331-6 (1998)). Thus,stabilization of SDF-1alpha through inhibition of DPP-IV would beexpected to decrease HIV infectivity.Hematopoiesis: DPP-IV inhibition may be useful for the treatment orprevention of hematopoiesis because DPP-IV may be involved inhematopoiesis. A DPP-IV inhibitor, Val-Boro-Pro, stimulatedhematopoiesis in a mouse model of cyclophosphamide-induced neutropenia(WO 99/56753).Neuronal Disorders: DPP-IV inhibition may be useful for the treatment orprevention of various neuronal or psychiatric disorders because a numberof peptides implicated in a variety of neuronal processes are cleaved invitro by DPP-IV. A DPP-IV inhibitor thus may have a therapeutic benefitin the treatment of neuronal disorders. Endomorphin-2, beta-casomorphin,and substance P have all been shown to be in vitro substrates forDPP-IV. In all cases, in vitro cleavage is highly efficient, withk_(cat)/K_(m) about10⁶ M⁻¹s⁻¹ or greater. In an electric shock jump test model of analgesiain rats, a DPP-IV inhibitor showed a significant effect that wasindependent of the presence of exogenous endomorphin-2 (Brain Research,815: 278-286 (1999)). Neuroprotective and neuroregenerative effects ofDPP-IV inhibitors were also evidenced by the inhibitors' ability toprotect motor neurons from excitotoxic cell death, to protect striatalinnervation of dopaminergic neurons when administered concurrently withMPTP, and to promote recovery of striatal innervation density when givenin a therapeutic manner following MPTP treatment [see Yong-Q. Wu, etal., “Neuroprotective Effects of Inhibitors of Dipeptidyl Peptidase-IVIn Vitro and In Vivo,” Int. Conf. On Dipeptidyl Aminopeptidases: BasicScience and Clinical Applications, Sep. 26-29, 2002 (Berlin, Germany)].Anxiety: Rats naturally deficient in DPP-IV have an anxiolytic phenotype(WO 02/34243; Karl et al., Physiol. Behav. 2003). DPP-IV deficient micealso have an anxiolytic phenotype using the porsolt and light/darkmodels. Thus DPP-IV inhibitors may prove useful for treating anxiety andrelated disorders.Memory and Cognition: GLP-1 agonists are active in models of learning(passive avoidance, Morris water maze) and neuronal injury(kainate-induced neuronal apoptosis) as demonstrated by During et al.(Nature Med. 9: 1173-1179 (2003)). The results suggest a physiologicalrole for GLP-1 in learning and neuroprotection. Stabilization of GLP-1by DPP-IV inhibitors are expected to show similar effects.Myocardial Infarction: GLP-1 has been shown to be beneficial whenadministered to patients following acute myocardial infarction(Circulation, 109: 962-965 (2004)). DPP-IV inhibitors are expected toshow similar effects through their ability to stabilize endogenousGLP-1.Tumor Invasion and Metastasis: DPP-IV inhibition may be useful for thetreatment or prevention of tumor invasion and metastasis because anincrease or decrease in expression of several ectopeptidases includingDPP-IV has been observed during the transformation of normal cells to amalignant phenotype (J. Exp. Med., 190: 301-305 (1999)). Up- ordown-regulation of these proteins appears to be tissue and cell-typespecific. For example, increased CD26/DPP-IV expression has beenobserved on T cell lymphoma, T cell acute lymphoblastic leukemia,cell-derived thyroid carcinomas, basal cell carcinomas, and breastcarcinomas. Thus, DPP-IV inhibitors may have utility in the treatment ofsuch carcinomas.Benign Prostatic Hypertrophy: DPP-IV inhibition may be useful for thetreatment of benign prostatic hypertrophy because increased DPP-IVactivity was noted in prostate tissue from patients with BPH (Eur. J.Clin. Chem. Clin. Biochem. 30: 333-338 (1992)).Sperm motility/male contraception: DPP-IV inhibition may be useful forthe altering sperm motility and for male contraception because inseminal fluid, prostatosomes, prostate derived organelles important forsperm motility, possess very high levels of DPP-IV activity (Eur. J.Clin. Chem. Clin. Biochem., 30: 333-338 (1992)).Gingivitis: DPP-IV inhibition may be useful for the treatment ofgingivitis because DPP-IV activity was found in gingival crevicularfluid and in some studies correlated with periodontal disease severity(Arch. Oral Biol., 37: 167-173 (1992)).Osteoporosis: DPP-IV inhibition may be useful for the treatment orprevention of osteoporosis because GIP receptors are present inosteoblasts.

The compounds of the present invention have utility in treating orpreventing one or more of the following conditions or diseases: (1)hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4)obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) irritable bowel syndrome, (15) inflammatorybowel disease, including Crohn's disease and ulcerative colitis, (16)other inflammatory conditions, (17) pancreatitis, (18) abdominalobesity, (19) neurodegenerative disease, (20) retinopathy, (21)nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarianhyperandrogenism (polycystic ovarian syndrome), (25) Type 2 diabetes,(26) growth hormone deficiency, (27) neutropenia, (28) neuronaldisorders, (29) tumor metastasis, (30) benign prostatic hypertrophy,(32) gingivitis, (33) hypertension, (34) osteoporosis, and otherconditions that may be treated or prevented by inhibition of DPP-IV.

The subject compounds are further useful in a method for the preventionor treatment of the aforementioned diseases, disorders and conditions incombination with other agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, suppression oramelioration of diseases or conditions for which compounds of Formula Ior the other drugs may have utility, where the combination of the drugstogether are safer or more effective than either drug alone. Such otherdrug(s) may be administered, by a route and in an amount commonly usedtherefor, contemporaneously or sequentially with a compound of FormulaI. When a compound of Formula I is used contemporaneously with one ormore other drugs, a pharmaceutical composition in unit dosage formcontaining such other drugs and the compound of Formula I is preferred.However, the combination therapy may also include therapies in which thecompound of Formula I and one or more other drugs are administered ondifferent overlapping schedules. It is also contemplated that when usedin combination with one or more other active ingredients, the compoundsof the present invention and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions of the present invention include those thatcontain one or more other active ingredients, in addition to a compoundof Formula I.

Examples of other active ingredients that may be administered incombination with a compound of Formula I, and either administeredseparately or in the same pharmaceutical composition, include, but arenot limited to:

(a) other dipeptidyl peptidase IV (DPP-IV) inhibitors;

(b) insulin sensitizers including (i) PPARγ agonists, such as theglitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555,rosiglitazone, balaglitazone, and the like) and other PPAR ligands,including PPARα/γ dual agonists, such as KRP-297, muraglitazar,naveglitazar, Galida, TAK-559, and PPARα agonists, such as fenofibricacid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate),(ii) biguanides such as metformin and phenformin, and (iii) proteintyrosine phosphatase-1B (PTP-1B) inhibitors;

(c) insulin or insulin mimetics;

(d) sulfonylureas and other insulin secretagogues, such as tolbutamide,glyburide, glipizide, glimepiride, and meglitinides, such as nateglinideand repaglinide;

(e) α-glucosidase inhibitors (such as acarbose and miglitol);

(f) glucagon receptor antagonists such as those disclosed in WO98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;

(g) GLP-1, GLP-1 analogues or mimetics, and GLP-1 receptor agonists,such as exendin-4 (exenatide), liraglutide (N,N-2211), CJC-1131,LY-307161, and those disclosed in WO 00/42026 and WO 00/59887;

(h) GIP and GIP mimetics, such as those disclosed in WO 00/58360, andGIP receptor agonists;

(i) PACAP, PACAP nimetics, and PACAP receptor agonists such as thosedisclosed in WO 01/23420;

(j) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin,atorvastatin, itavastatin, and rosuvastatin, and other statins), (ii)sequestrants (cholestyramine, colestipol, and dialkylaminoalkylderivatives of a cross-linked dextran), (iii) nicotinyl alcohol,nicotinic acid or a salt thereof, (iv) PPARα agonists such as fenofibricacid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate),(v) PPARα/γ dual agonists, such as KRP-297 and muraglitazar, (vi)inhibitors of cholesterol absorption, such as beta-sitosterol andezetimibe, (vii) acyl CoA:cholesterol acyltransferase inhibitors, suchas avasimibe, and (viii) anti-oxidants, such as probucol;

(k) PPARδ agonists, such as those disclosed in WO 97/28149;

(l) antiobesity compounds, such as fenfluramine, dexfenfluramine,phentermine, sibutramine, orlistat, neuropeptide Y₁ or Y₅ antagonists,CB1 receptor inverse agonists and antagonists, β₃ adrenergic receptoragonists, melanocortin-receptor agonists, in particular melanocortin-4receptor agonists, ghrelin antagonists, bombesin receptor agonists (suchas bombesin receptor subtype-3 agonists), and melanin-concentratinghormone (MCH) receptor antagonists;

(m) ileal bile acid transporter inhibitors;

(n) agents intended for use in inflammatory conditions such as aspirin,non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids,azulfidine, and selective cyclooxygenase-2 (COX-2) inhibitors;

(o) antihypertensive agents, such as ACE inhibitors (enalapril,lisinopril, captopril, quinapril, tandolapril), A-II receptor blockers(losartan, candesartan, irbesartan, valsartan, telmisartan, andeprosartan), beta blockers and calcium channel blockers;

(p) glucokinase activators (GKAs), such as those disclosed in WO03/015774;

(q) inhibitors of 11β-hydroxysteroid dehydrogenase type 1, such as thosedisclosed in U.S. Pat. No. 6,730,690;

(r) inhibitors of cholesteryl ester transfer protein (CETP), such astorcetrapib; and

(s) inhibitors of fructose 1,6-bisphosphatase, such as those disclosedin U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and6,489,476.

Dipeptidyl peptidase-IV inhibitors that can be combined with compoundsof structural formula I include those disclosed in WO 02/076450 (3 Oct.2002); WO 03/004498 (16 Jan. 2003); WO 03/004496 (16 Jan. 2003); EP 1258 476 (20 Nov. 2002); WO 02/083128 (24 Oct. 2002); WO 02/062764 (15Aug. 2002); WO 03/000250 (3 Jan. 2003); WO 03/002530 (9 Jan. 2003); WO03/002531 (9 Jan. 2003); WO 03/002553 (9 Jan. 2003); WO 03/002593 (9Jan. 2003); WO 03/000180 (3 Jan. 2003); WO 03/082817 (9 Oct. 2003); andWO 03/000181 (3 Jan. 2003). Specific DPP-IV inhibitor compounds includeisoleucine thiazolidide (P32/98); NVP-DPP-728; LAF 237; P93/01; and BMS477118.

Antiobesity compounds that can be combined with compounds of structuralformula I include fenfluramine, dexfenfluramine, phentermine,sibutramine, orlistat, neuropeptide Y₁ or Y₅ antagonists, cannabinoidCB1 receptor antagonists or inverse agonists, melanocortin receptoragonists, in particular, melanocortin-4 receptor agonists, ghrelinantagonists, bombesin receptor agonists, and melanin-concentratinghormone (MCH) receptor antagonists. For a review of anti-obesitycompounds that can be combined with compounds of structural formula I,see S. Chaki et al., “Recent advances in feeding suppressing agents:potential therapeutic strategy for the treatment of obesity,” ExpertOpin. Ther. Patents, 11: 1677-1692 (2001); D. Spanswick and K. Lee,“Emerging antiobesity drugs,” Expert Opin. Emerging Drugs, 8: 217-237(2003); and J. A. Fernandez-Lopez, et al., “Pharmacological Approachesfor the Treatment of Obesity,” Drugs, 62: 915-944 (2002).

Neuropeptide Y5 antagonists that can be combined with compounds ofstructural formula I include those disclosed in U.S. Pat. No. 6,335,345(1 Jan. 2002) and WO 01/14376 (1 Mar. 2001); and specific compoundsidentified as GW 59884A; GW 569180A; LY366377; and CGP-71683A.

Cannabinoid CB1 receptor antagonists that can be combined with compoundsof formula I include those disclosed in PCT Publication WO 03/007887;U.S. Pat. No. 5,624,941, such as rimonabant; PCT Publication WO02/076949, such as SLV-319; U.S. Pat. No. 6,028,084; PCT Publication WO98/41519; PCT Publication WO 00/10968; PCT Publication WO 99/02499; U.S.Pat. No. 5,532,237; U.S. Pat. No. 5,292,736; PCT Publication WO03/086288; PCT Publication WO 03/087037; and PCT Publication WO04/048317.

Melanocortin receptor agonists that can be combined with compounds ofstructural formula I include those disclosed in WO 03/009847 (6 Feb.2003); WO 02/068388 (6 Sep. 2002); WO 99/64002 (16 Dec. 1999); WO00/74679 (14 Dec. 2000); WO 01/70708 (27 Sep. 2001); and WO 01/70337 (27Sep. 2001) as well as those disclosed in J. D. Speake et al., “Recentadvances in the development of melanocortin-4 receptor agonists,” ExpertOpin. Ther. Patents, 12: 1631-1638 (2002).

The potential utility of safe and effective activators of glucokinase(GKAs) for the treatment of diabetes is discussed in J. Grimsby et al.,“Allosteric Activators of Glucokinase: Potential Role in DiabetesTherapy,” Science, 301: 370-373 (2003).

When a compound of the present invention is used contemporaneously withone or more other drugs, a pharmaceutical composition containing suchother drugs in addition to the compound of the present invention ispreferred. Accordingly, the pharmaceutical compositions of the presentinvention include those that also contain one or more other activeingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith another agent, the weight ratio of the compound of the presentinvention to the other agent will generally range from about 1000:1 toabout 1:1000, preferably about 200:1 to about 1:200. Combinations of acompound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed.(For purposes of this application, topical application shall includemouthwashes and gargles.)

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment or prevention of conditions which require inhibition ofdipeptidyl peptidase-IV enzyme activity an appropriate dosage level willgenerally be about 0.01 to 500 mg per kg patient body weight per daywhich can be administered in single or multiple doses. Preferably, thedosage level will be about 0.1 to about 250 mg/kg per day; morepreferably about 0.5 to about 100 mg/kg per day. A suitable dosage levelmay be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day,or about 0.1 to 50 mg/kg per day. Within this range the dosage may be0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration,the compositions are preferably provided in the form of tabletscontaining 1.0 to 1000 mg of the active ingredient, particularly 1.0,5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0,300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

When treating or preventing diabetes mellitus and/or hyperglycemia orhypertriglyceridemia or other diseases for which compounds of thepresent invention are indicated, generally satisfactory results areobtained when the compounds of the present invention are administered ata daily dosage of from about 0.1 mg to about 100 mg per kilogram ofanimal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Formost large mammals, the total daily dosage is from about 1.0 mg to about1000 mg, preferably from about 1 mg to about 50 mg. In the case of a 70kg adult human, the total daily dose will generally be from about 7 mgto about 350 mg. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Synthetic methods for preparing the compounds of the present inventionare illustrated in the following Schemes and Examples. Startingmaterials are commercially available or may be made according toprocedures known in the art or as illustrated herein.

The compounds of the present invention can be prepared fromintermediates such as those of formula II and a heteroaryl halide IIIusing standard coupling conditions followed by deprotection. Thepreparation of these intermediates is described in the followingSchemes, wherein Ar and R¹ are as defined above, X is Cl, Br, I,triflate, or some other leaving group, and P is a suitable nitrogenprotecting group such as tert-butoxycarbonyl (BOC), benzyloxycarbonyl(Cbz), and 9-fluorenylmethoxycarbonyl (Fmoc).

Compounds of formula IIa, wherein P is BOC, may be prepared fromintermediate 1 using a route described in Scheme 1. Deprotonation oflactam 1 with a base such as sodium hexamethyldisilazane followed byreaction with benzyl bromide provides the corresponding N-benzyl lactam.Subsequent hydrolysis of the methyl ester with, for example, lithiumhydroxide then provides acid 2. Acid 2 may then be subjected to Curtiusrearrangement following literature conditions (D. A. Evans, et al. J.Org. Chem., 64: 6411-6417 (1999)) to give the correspondingcarboxybenzyl carbamate, which is deprotected under hydrogenationconditions in the presence of di-tert-butyl dicarbonate to provideintermediate 3. Reduction of 3 using borane is followed by acidicwork-up and reprotection as the Boc derivative to provide 4. Removal ofthe benzyl protecting group by catalytic hydrogenation with, forexample, hydrogen gas and palladium hydroxide catalyst then providesintermediate IIa.

Compounds of formula IIb, wherein P is Cbz, may be prepared fromintermediate 1 using a route described in Scheme 2. Treatment of lactam1 with Meerwein's reagent (trimethyloxonium tetrafluoroborate) providesintermediate 5. Reduction of 5 with sodium borohydride and protection ofthe amine with, for example, di-tert-butyl dicarbonate provides N-Bocintermediate 6. Ester 6 may be hydrolyzed and then exposed to Curtiusrearrangement conditions described above in Scheme 1 to give 7.Deprotection under acidic conditions provides compound IIb.

Intermediates of formula 1 are known in the literature or may beconveniently prepared by a variety of methods familiar to those skilledin the art. One route described in the literature (W. H. Moos et al., J.Org. Chem., 46: 5064-5074 (1981)) is illustrated in Scheme 3. Asubstituted benzaldehyde 8 is treated with trimethyl or triethylphosphonoacetate 9 in the presence of a base such as1,8-diazobicyclo[5.4.0]undec-7-ene to provide the aryl enoate 10.Conjugate addition of ethyl or methyl cyanoacetate 11 to enoate 10 inthe presence of sodium methoxide provides 12 as a mixture ofstereoisomers at each chiral center. Reduction of the cyano group in 12using catalytic hydrogenation with, for example, hydrogen gas and aplatinum (IV) oxide catalyst, is followed by treatment of the productamine with basic methanol to induce cyclization and equilibration of thestereoisomers to predominantly the trans stereoisomer. This may befollowed by re-esterification of the intermediate using, for example,trimethylsilyldiazomethane to give compound 1 as predominantly the transisomer.

Intermediates III are commercially available, known in the literature,or conveniently prepared by a variety of methods familiar to thoseskilled in the art. Intermediates Ella may be prepared from3,6-dichloropyridazine 13 using a variation of a route described in theliterature (J. D. Albright, et. al. J. Med. Chem. 1981, 24, 592-600) asillustrated in Scheme 4. Alkyl or aryl hydrazides 14, which arecommercially available, known in the literature, or convenientlyprepared by a variety of methods familiar to those skilled in the art(K. M. Kahn, et. al. Bioorg. Med. Chem. 2003, 11, 1381-1387) are heatedwith 13 in a solvent such as ethanol to provide chloropyridazine-fusedtriazoles IIIa, wherein R² is defined above.

Intermediates IIIb may be prepared from 6-chloropyridazin-3-amine 15using a variation of a route described in the literature (E. Luraschi,et. al. Il Farmaco. 1997, 52, 213-217) as illustrated in Scheme 5.Substituted α-bromoketones 16, which are commercially available or knownin the literature, are heated with 15 in a solvent such as ethanol toprovide chloropyridazine-fused imidazoles IIIb, wherein R² is definedabove.

Intermediates IIIc may be prepared from 6-chloropyridazin-3-amine 15using a variation of a route described in the literature (C. Avellana,et. al. J. Heterocyclic Chem., 1977, 14, 325-327) as illustrated inScheme 6. Substituted acetoacetates 17, which are commercially availableor known in the literature, are heated with 15 in a solvent such asbenzyl alcohol to provide chloropyridazine-fused pyrimidones IIIc,wherein R² is defined above.

Compounds of Formula I may be prepared as illustrated in Scheme 7 fromintermediate II described above and intermediate III, wherein X is Cl,Br, I, triflate, or some other leaving group and R¹ is a heteroarylgroup, unsubstituted or substituted with one or more R² substituents, asdefined above. Intermediates III are known in the literature or may beconveniently prepared by a variety of methods familiar to those skilledin the art. Intermediates 18 may be prepared by heating II and IIItogether in the presence of a base such as triethylamine orN,N-diisopropylethylamine in solvents such as toluene,N,N-dimethylformamide (DMF), or ethylene glycol dimethyl ether (DME)according to procedures outlined in L. Toma, et. al. J. Med. Chem. 2002,45, 4011-4017 and references contained therein. The protecting group of18 is then removed with, for example, trifluoroacetic acid or methanolichydrogen chloride in the case of Boc to give the desired amine I.Alternatively, the protecting group may be removed with, for example,hydrogen bromide in acetic acid or catalytic hydrogenation in the caseof Cbz to give the desired amine I. The product is purified fromunwanted side products, if necessary, by crystallization, trituration,preparative thin layer chromatography, flash chromatography on silicagel, such as with a Biotage® apparatus, or HPLC. Compounds that arepurified by reverse phase HPLC may be isolated as the correspondingsalt. Purification of intermediates is achieved in the same manner.

In some cases the product I or synthetic intermediates illustrated inthe above schemes may be further modified, for example, by manipulationof substituents on Ar or R¹. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, arylation, acylation,condensation, addition, cyclization, and hydrolysis reactions that arecommonly known to those skilled in the art.

One such example is illustrated in Scheme 8. Intermediate 19 may beprepared by reaction of IIb and 2,4-dichloropyrimidine using thermalconditions described in Scheme 7. Further manipulation of intermediate19 may be accomplished using a palladium-catalyzed Suzuki coupling of 19with a boronic acid to provide intermediate 20. Deprotection of 20 maybe accomplished, for example, by treatment with hydrogen gas and acatalyst such as palladium on carbon in a solvent such as methanol orethyl acetate to provide compound I wherein R² is defined above.

Another such example is illustrated in Scheme 9. Intermediate 22 may beprepared by reaction of 2,6-dichloro-3-nitropyridine with a primaryamine such as methylamine in a solvent such as DMF with a base such assodium carbonate. Chloride 22 may then be coupled with IIa using thermalconditions described in Scheme 7 to afford aminopyridine 23. Furthermanipulation of intermediate 23 may be accomplished by reduction of thenitro group with, for example, hydrogen gas and a Raney nickel catalystto provide intermediate 24. Imidazole 25 may then be prepared by heatingdiamine 24 with an alkyl orthoformate such as trimethylorthoacetate.Deprotection of 25 may be accomplished, for example, by treatment withan acid such as trifluoroacetic acid or hydrochloric acid in a solventsuch as methanol, ethyl acetate, or dichloromethane to provide compoundI wherein R² is defined above.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided so that the inventionmight be more fully understood. These examples are illustrative only andshould not be construed as limiting the invention in any way.

Intermediate 1

Methyl-trans-6-oxo-4-(2,4,5-trifluorophenyl)piperidine-3-carboxylateStep A: Ethyl 3-(2,4,5-trifluorophenyl)acrylate

To a solution of 10 g (62 mmol) of 2,4,5-trifluorobenzaldehyde and 14 mL(70 mmol) of triethyl phosphonoacetate in 200 mL of tetrahydrofuran wasadded 11 mL (75 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene. Thesolution was stirred at ambient temperature for 4 h then concentrated invacuo and dissolved in 800 mL of a 10:1 solution of hexane/ethylacetate. The resulting solution was washed sequentially with 1Nhydrochloric acid, saturated aqueous sodium bicarbonate solution, andsaturated aqueous brine (200 mL each). The organic phase was then driedover magnesium sulfate, filtered, and evaporated in vacuo to yield acrude oil. The crude material was then purified by flash chromatographyon a Biotage Horizon® system (silica gel, 0 to 15% ethyl acetate/hexanesgradient) to give ethyl 3-(2,4,5-trifluorophenyl)acrylate as a colorlessoil. ¹H NMR (500 MHz, CDCl₃): δ 7.71 (d, J=16.2 Hz, 1H), 7.37 (ddd,J=17.1, 8.7, 1.8 Hz, 1H), 7.00 (ddd, J=16.2, 9.8, 2.4 Hz, 1H), 6.46 (d,J=16.2 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).

Step B: Dimethyl 2-cyano-3-(2,4,5-trifluorophenyl)pentanedioate

To a solution of 15 mL (64 mmol, 25% in methanol) of sodium methoxide in200 mL of methanol was added 5.5 mL (62 mmol) of methyl cyanoacetate andthe mixture was stirred at ambient temperature for 30 min. To thissolution was added 14 g (62 mmol) of the product of Step A in 50 mL ofmethanol and the resulting yellow mixture was heated to reflux for 6 h.The mixture was then quenched carefully at ambient temperature with 1Naqueous hydrochloric acid (100 mL) and concentrated to remove methanol.The resulting mixture was extracted with three 300-mL portions of ethylacetate, and the organic phases combined and washed sequentially with 1Nhydrochloric acid, saturated aqueous sodium bicarbonate solution, andsaturated aqueous brine (100 mL each). The organic phase was then driedover magnesium sulfate, filtered, and evaporated in vacuo to yield aviscous oil. The crude material was purified by flash chromatography ona Biotage Horizon® system (silica gel, 0 to 25% ethyl acetate/hexanesgradient) to give the title compound as a mixture of stereoisomers. ¹HNMR (500 MHz, CDCl₃): δ 7.33-6.96 (m, 2H), 4.23-3.93 (series of m, 2H),3.81-3.67 (series of s, 6H), 3.05-2.84 (m, 2H).

Step C:Methyl-trans-6-oxo-4-(2,4,5-trifluorophenyl)piperidine-3-carboxylate

To 450 mL of methanol at 0° C. was carefully added 30 mL of acetylchloride and the resulting solution was allowed to stir at ambienttemperature for 30 min. The resulting solution was added to 27 g (86mmol) of dimethyl 2-cyano-3-(2,4,5-trifluorophenyl)pentanedioate fromStep B and the reaction mixture was then shaken with 5.0 g of platinum(IV) oxide under 50 psi of hydrogen for 20 h. The mixture was filteredthrough a pad of Celite and the filter cake washed with methanol anddichloromethane. The combined filtrate and washings were concentratedand then taken up in 400 mL of 1:1 methanol/toluene with potassiumcarbonate (28 g, 200 mmol). The resulting mixture was heated to refluxfor 4 h, then cooled to 0° C. and carefully quenched with 1Nhydrochloric acid until the solution was acidic by pH paper. Theresulting mixture was then extracted with six 300-mL portions of 3:1chloroform/isopropyl alcohol and the organic phases combined and washedwith saturated aqueous brine (300 mL). The organic phase was then driedover magnesium sulfate, filtered, and evaporated in vacuo to yield acolorless solid. This crude material was dissolved in 500 mL of 1:1diethyl ether/methanol and cooled to 0° C. To this solution was added 75mL (150 mmol) of trimethylsilyldiazomethane solution (2M in hexanes) inportions until a yellow color persisted. After warming to ambienttemperature, the solution was stirred an additional 2 h, thenconcentrated in vacuo. The title compound was collected as a colorlesscrystalline solid which was used without further purification. LC/MS288.3 (M+1).

Intermediate 2

tert-Butyl [(3R,4R)-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamateStep A: Methyltrans-1-benzyl-6-oxo-4-(2,4,5-trifluorophenyl)piperidine-3-carboxylate

To a stirred solution of 8.0 g (28 mmol) of Intermediate 1 in 150 mL of5:1 tetrahydrofuran/N,N-dimethylformamide at −78° C. was added 32 mL (32mmol) of sodium bis(trimethylsilyl)amide (1M in tetrahydrofuran) and theresulting solution was stirred at −78° C. for 20 min. Benzyl bromide(4.2 mL, 35 mmol) was then added and the resulting solution was stirredat 0° C. for 60 min, then allowed to warm to ambient temperature over 12h. The mixture was quenched with 1N aqueous hydrochloric acid (100 mL)and concentrated to remove the tetrahydrofuran. The resulting mixturewas extracted with three 300-mL portions of ethyl acetate, and theorganic phases combined and washed sequentially with 1N hydrochloricacid, saturated aqueous sodium bicarbonate solution, and saturatedaqueous brine (100 mL each). The organic phase was dried over magnesiumsulfate, filtered, and evaporated in vacuo to yield a viscous oil. Thecrude material was purified by flash chromatography on a BiotageHorizon® system (silica gel, 0 to 50% ethyl acetate/hexanes gradient) togivemethyl-trans-1-benzyl-6-oxo-4-(2,4,5-trifluorophenyl)piperidine-3-carboxylate.LC/MS 378.4 (M+1).

Step B:trans-1-Benzyl-6-oxo-4-(2,4,5-trifluorophenyl)piperidine-3-carboxylicacid

To a solution of 8.4 g (22.2 mmol) ofmethyl-trans-1-benzyl-6-oxo-4-(2,4,5-trifluorophenyl)piperidine-3-carboxylatein 200 mL of 3:1 tetrahydrofuran/methanol was added 50 mL (50 mmol) of a1N aqueous lithium hydroxide solution and the resulting mixture wasstirred at 60° C. for 2 h. The solution was concentrated and acidifiedwith 100 mL of 1N aqueous hydrochloric acid. The resulting mixture wasthen extracted with three 250-mL portions of ethyl acetate, and theorganic phases combined and washed sequentially with 1N hydrochloricacid and saturated aqueous brine (200 mL each). The organic phase wasdried over magnesium sulfate, filtered, and evaporated in vacuo to yieldthe title acid as a colorless foamy solid that was used without furtherpurification. LC/MS 364.3 (M+1).

Step C: Methyl tert butyl[trans-1-benzyl-6-oxo-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

To 7.1 g (20 mmol) of the product of Step B in 150 mL of toluene wasadded 3.4 mL (24 mmol) of triethylamine followed by 4.7 mL (22 mmol) ofdiphenylphosphoryl azide. After stiffing at ambient temperature for 30min, the reaction mixture was warmed to 70° C. for 30 min, then slowlyheated to reflux for an additional 2 h. The reaction mixture was cooledto ambient temperature, 6.3 g (59 mmol) of benzyl alcohol was added, andthe reaction mixture was heated to reflux for 5 h. The solution was thencooled to ambient temperature and quenched with 1N aqueous hydrochloricacid (100 mL). The resulting mixture was extracted with four 200-mLportions of ethyl acetate, the organic phases combined and washedsequentially with 1N hydrochloric acid, saturated aqueous sodiumbicarbonate solution, and saturated aqueous brine (100 mL each). Theorganic phase was then dried over magnesium sulfate, filtered, andevaporated in vacuo to yield a viscous crude oil which contained benzylalcohol. This crude material was then dissolved in 150 mL of methanolwith 3.3 g (15 mmol) of di-tert-butyldicarbonate and the solution wasshaken with 1.0 g of palladium hydroxide (20% on carbon) under 45 psi ofhydrogen for 12 h. The mixture was filtered through a pad of Celite andthe filter cake washed with methanol and dichloromethane. The combinedfiltrate and washings were concentrated and purified by flashchromatography on a Biotage Horizon® system (silica gel, 0 to 60% ethylacetate/hexanes gradient) to give the title compound as a colorlesscrystalline solid. LC/MS 435.5 (M+1).

Step D: tert-Butyl[(3S,4S)-1-benzyl-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate andtert-butyl[(3R,4R)-1-benzyl-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

To 6.6 g (15 mmol) of the product of Step C in 50 mL of tetrahydrofuranwas added 45 mL (45 mmol) of borane (1M in THF) and the reaction mixturewas heated to reflux for 3 h. The reaction mixture was then cooled toambient temperature, 6N hydrochloric acid (50 mL) was added, and theresulting mixture was heated to reflux for an additional 2 h. Thereaction mixture was then cooled to ambient temperature and quenchedcarefully with 2N aqueous sodium hydroxide (about 180 mL) until thesolution was neutral by pH paper. Saturated aqueous sodium bicarbonatesolution (100 mL) was then added to the solution followed by 100 mL oftetrahydrofuran and 5.5 g (25 mmol) of di-tert-butyldicarbonate. Afterstirring at ambient temperature for 10 h, the solution was concentrated,then extracted with three 150-mL portions of ethyl acetate. The organicphases were combined and washed sequentially with saturated aqueoussodium bicarbonate solution and saturated aqueous brine (100 mL each).The organic phase was then dried over magnesium sulfate, filtered, andevaporated in vacuo to yield a crude oil, which was purified by flashchromatography on a Biotage Horizon® system (silica gel, 0 to 40% ethylacetate/hexanes gradient) to give the title compound as a colorlesscrystalline solid. Chiral HPLC separation (ChiralCel AD column, 5%isopropyl alcohol/heptane) gave the 3S, 4S enantiomer A as the moremobile eluting compound and the 3R, 4R enantiomer B, as the less mobileeluting compound. For A: LC/MS 421.5 (M+1). For B: LC/MS 421.5 (M+1).

Step E: tert-Butyl[(3R,4R)-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

A solution of 2.3 g (5.5 mmol) of enantiomer B from Step D in 80 mL ofmethanol was stirred with 1.0 g of palladium hydroxide (20% on carbon)under 1 atmosphere of hydrogen at ambient temperature for 12 h. Themixture was filtered through a pad of Celite and the filter cake washedwith methanol and dichloromethane. The combined filtrate and washingswere concentrated and used without further purification to giveIntermediate 2 as a colorless crystalline solid. LC/MS 331.3 (M+1).

Intermediate 3

Benzyl [(3R,4R)-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate StepA: Methyl(3R,4S)-6-methoxy-4-(2,4,5-trifluorophenyl)-2,3,4,5-tetrahydropyridine-3-carboxylateand methyl(3S,4R)-6-methoxy-4-(2,4,5-trifluorophenyl)-2,3,4,5-tetrahydropyridine-3-carboxylate

To a stirred solution of 20 g (69 mmol) of Intermediate 1 in 200 mL ofdichloromethane was added 13 g (85 mmol) of trimethyloxoniumtetrafluoroborate and the resulting mixture was stirred at ambienttemperature for 15 h. The mixture was next cooled to 0° C. and thenquenched with saturated aqueous sodium bicarbonate solution (300 mL).The resulting mixture was extracted with three 300-mL portions ofdichloromethane, and the organic phases combined and washed sequentiallywith saturated aqueous sodium bicarbonate solution and saturated aqueousbrine (200 mL each). The organic phase was then dried over magnesiumsulfate, filtered, and evaporated in vacuo. The crude crystalline solidwas then purified by flash chromatography on a Biotage Horizon® system(silica gel, 20 to 100% ethyl acetate/hexanes gradient) to give methyltrans-6-methoxy-4-(2,4,5-trifluorophenyl)-2,3,4,5-tetrahydropyridine-3-carboxylateas a colorless crystalline solid along with recovered starting material.Chiral HPLC separation (ChiralCel AD column, 3% isopropylalcohol/heptane) gave the 3R, 4S enantiomer A, as the more mobileeluting compound and the 3S, 4R enantiomer B as the less mobile elutingcompound. For A: LC/MS 302.3 (M+1). For B: LC/MS 302.3 (M+1).

Step B: 1-tert-Butyl 3-methyl(3R,4S)-4-(2,4,5-trifluorophenyl)piperidine-1,3-dicarboxylate

To 5.0 g (17 mmol) of enantiomer A of Step A in 200 mL of ethanol wasadded 5.0 g (132 mmol) of sodium borohydride and the resulting mixturewas stirred at ambient temperature for 14 h. The reaction mixture wasthen quenched carefully with 3N aqueous phosphoric acid (50 mL).Potassium carbonate was then added until the solution was neutral by pHpaper, then an additional 100 mL of saturated aqueous sodium bicarbonatesolution was added with 200 mL of tetrahydrofuran and 6.5 g (30 mmol) ofdi-tert-butyldicarbonate. After stirring at ambient temperature for 6 h,the mixture was extracted with three 150-mL portions of ethyl acetate,and the organic phases combined and washed sequentially with 1Nhydrochloric acid, saturated aqueous sodium bicarbonate solution, andsaturated aqueous brine (100 mL each). The organic phase was then driedover magnesium sulfate, filtered, and evaporated in vacuo to yield aviscous oil. This crude material was then purified by flashchromatography on a Biotage Horizon® system (silica gel, 0 to 40% ethylacetate/hexanes gradient) to give the title compound as a colorless oil.LC/MS 396.3 (M+23).

Step C:(3R,4S)-1-(tert-Butoxycarbonyl)-4-(2,4,5-trifluorophenyl)piperidine-3-carboxylicAcid

To 3.3 g (15 mmol) of the product of Step B in 200 mL of 3:1tetrahydrofuran/methanol was added 50 mL (50 mmol) of 1N aqueous lithiumhydroxide solution and the resulting solution was stirred at ambienttemperature for 16 h, then concentrated and acidified with 100 mL of 1Naqueous hydrochloric acid. The resulting mixture was extracted withthree 100-mL portions of ethyl acetate, and the organic phases combinedand washed sequentially with 1N hydrochloric acid and saturated aqueousbrine (100 mL each). The organic phase was dried over magnesium sulfate,filtered, and evaporated in vacuo to yield the title compound as acolorless foamy solid that was used without further purification. LC/MS382.4 (M+23).

Step D: tert-Butyl(3R,4R)-3-{[(benzyloxy)carbonyl]amino}-4-(2,4,5-trifluorophenyl)piperidine-1-carboxylate

To 2.8 g (7.8 mmol) of the product of Step C in 50 mL of toluene wasadded 1.3 mL (9.0 mmol) of triethylamine followed by 1.9 mL (9.0 mmol)of diphenylphosphoryl azide. After stirring at ambient temperature for30 min, the reaction mixture was warmed to 70° C. for 30 min then slowlyheated to reflux for an additional 2 h. The reaction mixture was thencooled to ambient temperature and 2.4 mL (22 mmol) of benzyl alcohol wasadded. The reaction mixture was heated to reflux for 5 h then cooled toambient temperature and quenched with 1N aqueous hydrochloric acid (100mL). The resulting mixture was extracted with three 150-mL portions ofethyl acetate, and the organic phases combined and washed sequentiallywith 1N hydrochloric acid, saturated aqueous sodium bicarbonatesolution, and saturated aqueous brine (70 mL each). The organic phasewas then dried over magnesium sulfate, filtered, and evaporated in vacuoto yield a viscous crude oil which was purified by flash chromatographyon a Biotage Horizon® system (silica gel, 0 to 30% ethyl acetate/hexanesgradient) to give the title compound as a viscous oil. LC/MS 365.3(M-Boc).

Step E: Benzyl[(3R,4R)-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

The product from Step D was dissolved into 40 ml of 1:1dichloromethane/trifluoroacetic acid and stirred at ambient temperaturefor 60 min. The solution was then concentrated and taken up in 250 mL of3:1 chloroform/isopropyl alcohol then washed with saturated aqueoussodium bicarbonate solution, and saturated aqueous brine (100 mL each).The organic phase was then dried over magnesium sulfate, filtered, andevaporated in vacuo to yield the title compound as a colorlesscrystalline solid which was used without further purification. LC/MS365.4 (M+1).

Intermediate 4

6-Chloro-3-methyl[1,2,4]triazolo[4,3-b]pyridazine

To a stirred solution of 1.0 g (6.7 mmol) of 3,6-dichloropyridazine in 5mL of butanol was added 500 mg (6.7 mmol) of acetic hydrazide and theresulting solution was stirred under nitrogen at reflux for 24 h. Thereaction mixture was then cooled to ambient temperature, filtered, andthe resulting precipitate washed with ethyl acetate and methanol. Thecombined filtrate and washings were concentrated and dissolved in 250 mLof 10:1 chloroform/methanol then washed with saturated aqueous brine(2×100 mL). The organic phase was then dried over magnesium sulfate,filtered, and evaporated in vacuo to yield a yellow solid. The crudematerial was purified by flash chromatography on a Biotage Horizon®system (silica gel, 0 to 80% ethyl acetate/hexanes gradient) to give thetitle compound as a brown crystalline solid. LC/MS 169.0 (M+1).

Intermediate 5

6-Chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazine

Intermediate 5 may be prepared using a similar route described in theliterature (C. Enguehard, et. al. Synthesis, 2001, 4, 595-600). Asolution of 1.0 g (7.7 mmol) of 6-chloropyridazin-3-amine and 1.0 mL (10mmol) 3-bromo-1,1,1-trifluoroacetone in 10 mL ethanol was heated toreflux for 5 h. The resulting mixture was cooled to ambient temperatureand evaporated in vacuo to yield a viscous oil which was then taken upin saturated aqueous sodium carbonate until the solution was basic by pHpaper. The aqueous phase was extracted with three 50 mL portions ofdichloromethane, and the organic phases then combined, dried overmagnesium sulfate, filtered and evaporated in vacuo to yield a yellowsolid. The crude material was purified by flash chromatography on aBiotage Horizon® system (silica gel, 0 to 40% ethyl acetate/hexanesgradient) to give Intermediate 5 as a yellow crystalline solid. LC/MS222.3 (M+1).

Intermediate 6

6-Chloro-2H-[1,2,4]thiadiazolo[2,3-b]pyridazin-2-one

Intermediate 6 was prepared using a synthetic route described in theliterature (K. Pilgram, et. al. J. Org. Chem. 1973, 38, 1575-1578).LC/MS 188.1 (M+1).

Intermediate 7

6-Chloro-2-(trifluoromethyl)[1,2,4]triazolo[1,5-b]pyridazine Step A:N-(6-Chloropyridazin-3-yl)-2,2,2-trifluoroacetamide

To a solution of 2 g (15 mmol) of 6-chloropyridazin-3-amine and 2.4 mL(17 mmol) of triethylamine in 150 mL dichloromethane at 0° C. wascarefully added 2.1 mL (15 mmol) trifluoroacetic acid anhydride. Theresulting solution was allowed to warm to ambient temperature thenconcentrated in vacuo and dissolved in 200 mL of a 3:1 solution ofchloroform/isopropanol. The resulting solution was washed sequentiallywith saturated aqueous sodium bicarbonate solution and saturated aqueousbrine (200 mL each). The organic phase was then dried over magnesiumsulfate, filtered, and evaporated in vacuo to yield a crude oil whichwas carried forward without purification.

Step B: (1Z)-N-(6-Chloropyridazin-3-yl)-2,2,2-trifluoroethanimidoylchloride

A solution of 3.8 g (17 mmol) of the crude product of Step A and 4.2 g(22 mmol) of phosphorous pentachloride in 200 mL of dichloroethane washeated at reflux temperature under nitrogen. After 6 h the reaction wascooled to ambient temperature then concentrated in vacuo to yield acrude oil which was carried on to Step C.

Step C:(1Z)-N-(6-Chloropyridazin-3-yl)-2,2,2-trifluoro-N′-hydroxyethanimidamide

To a solution of 4.5 g (18 mmol) of the crude product of Step B in 150mL tetrahydrofuran was carefully added 2 mL aqueous 50% methoxyamine.The resulting solution was stirred under nitrogen at ambienttemperature. After 1 h the solution was concentrated in vacuo thendissolved in 100 mL ethyl acetate and washed sequentially with saturatedaqueous sodium bicarbonate solution and saturated aqueous brine (100 mLeach). The organic phase was then dried over magnesium sulfate,filtered, and evaporated in vacuo to yield a crude oil.

Step D: 6-Chloro-2-(trifluoromethyl)[1,2,4]triazolo[1,5-b]pyridazine

To 2.2 g (9.0 mmol) crude product of Step C was added 2 mL concentratedpolyphosphoric acid and the resulting mixture was stirred under nitrogenat 150° C. for 4 h. The reaction mixture was then cooled to 0° C. andquenched carefully with concentrated ammonium hydroxide until thesolution was basic by pH paper. The resulting solution was thenextracted with three 100 mL portions of ethyl acetate, and the organicphases combined and washed with 250 mL saturated aqueous brine. Theorganic phase was then dried over magnesium sulfate, filtered, andevaporated in vacuo to yield a crude oil. The crude material waspurified by flash chromatography on a Biotage Horizon® system (silicagel, 0 to 80% ethyl acetate/hexanes gradient) to give Intermediate 7 asa yellow crystalline solid. LC/MS 223.2 (M+1).

Intermediate 8

7-Chloro-2-fluoro-3-methyl-4H-pyrimido[1,2-b]pyridazin-4-one

Intermediate 8 may be prepared using a variation of a route described inthe literature (C. Avellana, et. al. J. Heterocyclic Chem., 1977, 14,325-327). To a stirred solution of 1.0 g (7.7 mmol) of6-chloropyridazin-3-amine in 5 mL benzyl alcohol was added 1.4 mL (11.6mmol) ethyl 2-fluoroacetoacetate. The resulting solution was refluxedfor 24 h then evaporated in vacuo to yield a crude solid which waspurified by flash chromatography on a Biotage Horizon® system (silicagel, 0 to 80% ethyl acetate/hexanes gradient) to give Intermediate 8 asa brown crystalline solid. LC/MS 214.2 (M+1).

Intermediate 9

6-Chloro-2-methyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one Step A:6-Chloro[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one

To a stirring solution of 3 g (20 mmol) of 3,6-dichloropyridazine and4.5 g (40 mmol) semicarbazide hydrochloride in 100 mL of a 3:1 mixtureof ethanol/water was added 5 drops of concentrated hydrochloric acid.The resulting solution was heated to reflux for 24 h under nitrogen thenevaporated in vacuo and the resulting solid was recrystallized fromethanol to yield the title compound as a yellow crystalline solid. Asimilar route to this compound is described in the literature (P.Francavilla, et. al. J. Heterocyclic Chem., 1971, 8, 415-419). LC/MS171.2 (M+1).

Step B: 6-Chloro-2-methyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one

To a stirred solution of 150 mg (0.88 mmol) of the product of Step A in10 mL of 5:1 tetrahydrofuran/N,N-dimethylformamide at −78° C. was added0.88 mL (0.88 mmol) of sodium bis(trimethylsilyl)amide (1M intetrahydrofuran) and the resulting solution was stirred at −78° C. for30 min. Methyl iodide (0.120 mL, 1.9 mmol) was then added and theresulting solution was stirred at 0° C. for 1 h, then allowed to warm toambient temperature over 24 h. The resulting mixture was extracted withthree 20 mL portions of ethyl acetate, and the organic phases combinedand washed sequentially with 1N hydrochloric acid, saturated aqueoussodium bicarbonate solution, and saturated aqueous brine (75 mL each).The organic phase was dried over magnesium sulfate, filtered, andevaporated in vacuo to yield a viscous oil. The crude material waspurified by flash chromatography on a Biotage Horizon® system (silicagel, 0 to 80% ethyl acetate/hexanes gradient) to give Intermediate 9.LC/MS 184.6 (M+1).

Intermediate 10

2-Bromopyrazino[2,3-b]pyrazine

To a stirred solution of 50 mg (0.27 mmol) of5-bromopyrazine-2,3-diamine in 2 mL of a 10:1 solution ofmethanol/acetic acid was added 0.046 mL (0.40 mmol) of glyoxal solution(40 wt. % in water) and the resulting solution was stirred at 50° C. for4 h. The reaction mixture was cooled to ambient temperature, dilutedwith 10 mL of ethyl acetate and washed with saturated aqueous sodiumbicarbonate solution, and saturated aqueous brine (5 mL each). Theorganic phase was then dried over anhydrous sodium sulfate, filtered,and evaporated in vacuo to yield the title compound as a tan crystallinesolid which was used without further purification. LC/MS 211.1, 213.1(M+1, M+3).

Example 1

(3R,4R)-1-Pyrimidin-4-yl-4-(2,4,5-trifluorophenyl)piperidin-3-aminebis-trifluoroacetic acid salt Step A: Benzyl[(3R,4R)-1-(6-chloropyrimidin-4-yl)-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

A solution of 50 mg (0.14 mmol) of Intermediate 3 and 100 mg (0.67 mmol)of 4,6-dichloropyrimidine in 6 mL of 5:1 toluene/N,N-dimethylformamidewas heated at reflux temperature under nitrogen. After 48 h the reactionwas cooled to ambient temperature and subsequently diluted with 10 mL ofethyl acetate. The solution was then washed with saturated sodiumbicarbonate solution and saturated aqueous brine (10 mL each). Theorganic phase was then dried over magnesium sulfate, filtered, andevaporated in vacuo to yield a crude oil, which was purified by reversephase HPLC (YMC Pro-C18 column, gradient elution, 10 to 90%acetonitrile/water with 0.1% TFA) to afford the title compound as acolorless crystalline solid. LC/MS 477.3 (M+1).

Step B:(3R,4R)-1-Pyrimidin-4-yl-4-(2,4,5-trifluorophenyl)piperidin-3-aminebis-trifluoroacetic acid salt

To 40 mg (0.084 mmol) of the product of Step A in 4 mL of 3:1 ethylacetate/methanol was added 50 mg of 10% palladium on carbon. Afterstirring at ambient temperature for 4 h under 1 atmosphere of hydrogen,the reaction was filtered through a pad of Celite and the filter cakewashed with dichloromethane. The combined filtrate and washings wereconcentrated and the crude material was purified by reverse phase HPLC(YMC Pro-C18 column, gradient elution, 0 to 80% acetonitrile/water with0.1% TFA) to afford the title compound as a colorless crystalline solid.LC/MS 309.3 (M+1).

Example 2

(3R,4R)-1-[6-(4-fluorophenyl)pyridazin-3-yl]-4-(2,4,5-trifluorophenyl)piperidin-3-aminebis-trifluoroacetic acid salt Step A: Benzyl[(3R,4R)-1-(6-chloropyridazin-3-yl)-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

A solution of 120 mg (0.33 mmol) of Intermediate 3 and 180 mg (1.2 mmol)of 3,6-dichloropyridazine in 6 mL of 5:1 toluene/N,N-dimethylformamidewas heated at reflux temperature under nitrogen. After 24 h the reactionwas cooled to ambient temperature and subsequently diluted with 10 mL ofethyl acetate. The solution was then washed with saturated sodiumbicarbonate solution and saturated aqueous brine (10 mL each). Theorganic phase was then dried over magnesium sulfate, filtered, andevaporated in vacuo to yield a crude oil, which was purified by reversephase HPLC (YMC Pro-C18 column, gradient elution, 10 to 90%acetonitrile/water with 0.1% TFA) to afford the title compound as acolorless crystalline solid. LC/MS 477.2 (M+1).

Step B: Benzyl[(3R,4R)-1-[6-(4-fluorophenyl)pyridazin-3-yl]-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

To a solution of 58 mg (0.12 mmol) of the product of Step A and 27 mg(0.19 mmol) of 4-fluorophenylboronic acid in 4 mL of 1:1 ethanol/toluenewas added 0.60 mL (1.2 mmol) 2N aqueous sodium carbonate solutionfollowed by 200 mg (0.245 mmol) of[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II). Theresulting solution was stirred under nitrogen at 100° C. for 24 h, thenallowed to cool to ambient temperature. The reaction mixture was thenfiltered through a pad of Celite and the filter cake washed with ethylacetate and methanol. The combined filtrate and washings wereconcentrated and the crude material was purified by reverse phase HPLC(YMC Pro-C18 column, gradient elution, 10 to 90% acetonitrile/water with0.1% TFA) to afford the title compound as a yellow oil. LC/MS 537.3(M+1).

Step C:(3R,4R)-1-[6-(4-fluorophenyl)pyridazin-3-yl]-4-(2,4,5-trifluorophenyl)piperidin-3-aminebis-trifluoroacetic acid salt

To 38 mg (0.071 mmol) of the product of Step B was added 3 mL of 30%hydrogen bromide in acetic acid, and the solution was allowed to stir atambient temperature for 1 h. The resulting solution was then evaporatedin vacuo to yield a viscous crude oil which was purified by reversephase HPLC (YMC Pro-C18 column, gradient elution, 0 to 80%acetonitrile/water with 0.1% TFA) to afford the title compound as acolorless crystalline solid. LC/MS 403.2 (M+1).

Example 3

(3R,4R)-1-(3-Methyl[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-(2,4,5-trifluorophenyl)piperidin-3-aminebis-trifluoroacetic acid salt Step A: tert-Butyl[(3R,4R)-1-(3-methyl[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

To a solution of 50 mg (0.15 mmol) of Intermediate 2 and 64 mg (0.38mmol) of Intermediate 4 in 2 mL toluene was added 0.032 mL (0.23 mmol)of triethylamine and the resulting solution was heated at refluxtemperature under nitrogen. After 24 h the reaction was cooled toambient temperature and subsequently diluted with 10 mL of ethylacetate. The solution was then washed with saturated sodium bicarbonatesolution and saturated aqueous brine (10 mL each). The organic phase wasthen dried over magnesium sulfate, filtered, and evaporated in vacuo toyield a crude oil, which was purified by reverse phase HPLC (YMC Pro-C18column, gradient elution, 10 to 90% acetonitrile/water with 0.1% TPA) toafford the title compound as a colorless crystalline solid. LC/MS 463.4(M+1).

Step B:(3R,4R)-1-(3-Methyl[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-(2,4,5-trifluorophenyl)piperidin-3-aminebis-trifluoroacetic acid salt

The product from Step A (24 mg, 0.067 mmol) was dissolved in 10 mL of1:1 dichloromethane/trifluoroacetic acid and stirred at ambienttemperature for 60 min. The solution was then concentrated to yield aviscous crude oil which was purified by reverse phase HPLC (YMC Pro-C18column, gradient elution, 0 to 80% acetonitrile/water with 0.1% TFA) toafford the title compound as a colorless crystalline solid. LC/MS 363.4(M+1).

Example 4

6-[(3R,4R)-3-Amino-4-(2,4,5-trifluorophenyl)piperidin-1-yl]-2-methylpyrido[3,2-d]pyrimidin-4(3H)-onebis-trifluoroacetic acid salt Step A:tert-Butyl[(3R,4R)-1-[6-(aminocarbonyl)-5-nitropyridin-2-yl]-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

To a solution of 700 mg (2.1 mmol) of Intermediate 2 and 770 mg (4.2mmol) of 6-chloro-3-nitropyridine-2-carboxamide (prepared as in G. W.Rewcastle, et. al. J. Med. Chem. 1996, 39, 1823-1835) in 8 mL of tolueneand 4 mL of N,N-dimethylformamide was added 1.7 mL (10.6 mmol) ofN,N-diisopropylethylamine and the solution was stirred under nitrogen atreflux for 30 h. The reaction mixture was then cooled to ambienttemperature, diluted with 15 mL of methylene chloride and poured into100 mL of a saturated aqueous bicarbonate solution. The layers wereseparated and the aqueous layer extracted with three 100 mL portions ofmethylene chloride and the combined organic phases were dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to yield ayellow solid. The yellow solid was purified by flash chromatography on aBiotage Horizon® system (silica gel, 0 to 70% ethyl acetate/hexanesgradient) to give the title compound as a yellow crystalline solid.LC/MS 496.6 (M+1).

Step B:tert-Butyl[(3R,4R)-1-[5-amino-6-(aminocarbonyl)pyridin-2-yl]-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

To 993 mg (2.0 mmol) of the product of Step A in 40 mL of 3:1methanol/tetrahydrofuran at 0° C. was added 166 mg (0.70 mmol) of nickel(II) chloride hexahydrate followed by 318 mg (8.4 mmol) of sodiumborohydride in portions over 30 min. The reaction mixture was stirredfor an additional 30 min and then quenched with 100 mL of a saturatedaqueous sodium bicarbonate solution. The layers were separated and theaqueous phase extracted with three 100-mL portions of 3:1chloroform/isopropyl alcohol. The combined organic phases were driedover anhydrous magnesium sulfate, filtered and evaporated in vacuo toyield a yellow solid which was purified by flash chromatography on aBiotage Horizon® system (silica gel, 0 to 100% ethyl acetate/hexanesgradient) to give the title compound as a yellow crystalline solid.LC/MS 465.6 (M+1).

Step C:tert-Butyl[(3R,4R)-1-1(2-methyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidine-6-yl)-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

To 20 mg (0.04 mmol) of the product from Step B in 1 mL of toluene wasadded 0.08 mL (0.4 mmol) triethyl orthoacetate and the resultingsolution was stirred under nitrogen at reflux for 48 h. The reactionmixture was then cooled to ambient temperature and diluted with 10 mL ofa 1:1 solution of methylene chloride/saturated aqueous sodiumbicarbonate solution. The layers were separated and the aqueous layerextracted with three 5-mL portions of methylene chloride, and theorganic phases combined and dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to yield a viscous crude oil. Thecrude oil was purified by preparative thin layer chromatography using anAnaltech® 1000 micron plate (ethyl acetate solvent) to give the titlecompound as a viscous oil. LC/MS 490.1 (M+1).

Step D:6-[(3R,4R)-3-Amino-4-(2,4,5-trifluorophenyl)piperidin-1-yl]-2-methylpyrido[3,2-d]pyrimidin-4(3H)-onebis-trifluoroacetic acid salt

T/he product from Step C (10 mg, 0.02 mmol) was dissolved in 4 mL of 1:1dichloromethane/trifluoroacetic acid and stirred at ambient temperaturefor 60 min. The solution was then concentrated to yield a viscous crudeoil which was purified by reverse phase HPLC (YMC Pro-C18 column,gradient elution, 0 to 80% acetonitrile/water with 0.1% TFA) to affordthe title compound as a colorless crystalline solid. LC/MS 390.1 (M+1).

Example 5

(3R,4R)-1-3-(3-Methylpyrido[2,3-b]pyrazin-6-yl)-4-(2,4,5-trifluorophenyl)piperidin-3-aminebis-trifluoroacetic acid salt Step A: tert-Butyl[(3R,4R)-1-(6-amino-5-nitropyridin-2-yl)-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

To a solution of 200 mg (0.6 mmol) of Intermediate 2 and 115 mg (0.66mmol) of 6-chloro-3-nitropyridin-2-amine in 8 mL of toluene was added0.21 mL (1.2 mmol) of N,N-diisopropylethylamine and the solution wasstirred under nitrogen at reflux for 5 h. The reaction mixture was thencooled to ambient temperature, diluted with 15 mL of methylene chlorideand poured into 15 mL of a saturated aqueous bicarbonate solution. Thelayers were separated and the aqueous layer extracted with three 15 mLportions of methylene chloride and the combined organic phases weredried over anhydrous sodium sulfate, filtered and evaporated in vacuo toyield a yellow solid. The yellow solid was purified by flashchromatography on a Biotage Horizon® system (silica gel, 0 to 60% ethylacetate/hexanes gradient) to give the title compound as a yellowcrystalline solid. LC/MS 468.2 (M+1).

Step B: tert-Butyl[(3R,4R)-1-(5,6-diaminopyridin-2-yl)-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

To 85 mg (0.18 mmol) of the product of Step A in 4 mL of 3:1methanol/tetrahydrofuran at 0° C. was added 2.5 mg (0.01 mmol) of nickel(II) chloride hexahydrate followed by 40 mg (1.0 mmol) of sodiumborohydride in four 10 mg portions every 5 min. The reaction mixture wasstirred for an additional 10 min and poured into 20 mL of a 1:1 mixtureof methylene chloride/saturated aqueous ammonium chloride solution. Thelayers were separated and the aqueous phase extracted with three 10-mLportions of methylene chloride. The combined organic phases were driedover anhydrous sodium sulfate, filtered and evaporated in vacuo to yielda purple solid which was purified by preparative thin layerchromatography using an Analtech® 1500 micron plate (1:2 hexane/ethylacetate solvent) to give the title compound as a purple crystallinesolid. LC/MS 438.1 (M+1).

Step C: tert-Butyl[(3R,4R)-1-(3-methylpyrido[2,3-b]pyrazin-6-yl)-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

To 40 mg (0.09 mmol) of the product of Step B in 2 mL of methanol wasadded 0.07 mL (0.46 mmol) of 2-oxopropanal solution (40 wt. % in water)and stirred at ambient temperature for 1 h. The reaction mixture wasthen, diluted with 10 mL of methylene chloride and poured into 10 mL ofa saturated aqueous bicarbonate solution. The layers were separated andthe aqueous layer extracted with three 10 mL portions of methylenechloride and the combined organic phases were dried over anhydroussodium sulfate, filtered and evaporated in vacuo to yield a tan solidwhich was purified by preparative thin layer chromatography using anAnaltech® 1500 micron plate (1:3 hexane/ethyl acetate solvent) to givethe title compound as a tan crystalline solid. LC/MS 474.1 (M+1).

Step D:(3R,4R)-1-3-(3-Methylpyrido[2,3-b]pyrazin-6yl)-4-(2,4,5-trifluorophenyl)piperidin-3-aminebis-trifluoroacetic acid salt

The product from Step C (5 mg, 0.01 mmol) was dissolved in 4 mL of 1:1dichloromethane/trifluoroacetic acid and stirred at ambient temperaturefor 60 min. The solution was then concentrated to yield a viscous crudeoil which was purified by reverse phase HPLC (YMC Pro-C18 column,gradient elution, 0 to 80% acetonitrile/water with 0.1% TFA) to affordthe title compound as a colorless crystalline solid. LC/MS 374.1 (M+1).

Example 6

(3R,4R)-1-(2,3-Dimethyl-3H-imidazo[4,5-b]pyridin-5-yl)-4-(2,4,5-trifluorophenyl)piperidin-3-aminebis-trifluoroacetic acid salt Step A:6-Chloro-N-methyl-3-nitropyridin-2-amine

To a stirred solution of 10 g (52 mmol) of 2,6-dichloro-3-nitropyridinein 300 mL of N,N-dimethylformamide was added 26 mL (52 mmol) ofmethylamine (2M in tetrahydrofuran) and 9.3 g (88 mmol) of sodiumcarbonate and the resulting mixture was stirred for 24 h. The solutionwas diluted with 500 mL water and extracted with three 700 mL portionsof ethyl acetate. The organic phase was dried over magnesium sulfate,filtered, and evaporated in vacuo to yield a viscous oil. The crudematerial was purified by flash chromatography on a Biotage Horizon®system (silica gel, 0 to 10% ethyl acetate/hexanes gradient) to give6-chloro-N-methyl-3-nitropyridin-2-amine as a yellow solid. LC/MS 188.1(M+1).

Step B:tert-Butyl[(3R,4R)-1-[6-(methylamino)-5-nitropyridin-2-yl]-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

To a solution of 300 mg (0.9 mmol) of Intermediate 2 and 206 mg (1.1mmol) 6-chloro-N-methyl-3-nitropyridin-2-amine in 5 mL toluene was added0.33 mL (1.4 mmol) of N,N-diisopropylethylamine and the solution wasstirred under nitrogen at reflux for 24 h. The reaction mixture was thencooled to ambient temperature, diluted with 25 mL ethyl acetate, andwashed sequentially with saturated aqueous sodium bicarbonate solutionand saturated aqueous brine (25 mL each). The organic phase was thendried over magnesium sulfate, filtered, and evaporated in vacuo to yielda yellow solid which was purified by reverse phase HPLC (YMC Pro-C18column, gradient elution, 10-90% acetonitrile/water with 0.1%trifluoroacetic acid) to afford the title compound as a yellowcrystalline solid.

Step C:tert-Butyl[(3R,4R)-1-[5-amino-6-(methylamino)pyridine-2-yl]-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

To a stirring solution of 68 mg (0.14 mmol) of the product of Step B in8 mL of 10:1 tetrahydrofuran/methanol under nitrogen was added 0.20 mLRaney Nickel (slurry in water). The resulting mixture under hydrogen washeated at 40° C. for 1 h and then cooled to ambient temperature over 24h. The mixture was then filtered through a pad of Celite and the filtercake washed with dichloromethane and methanol. The combined filtrate andwashings were concentrated in vacuo and the resulting purple solid waspurified by reverse phase HPLC (YMC Pro-C18 column, gradient elution,10-90% acetonitrile/water with 0.1% trifluoroacetic acid) to afford thetitle compound as a purple crystalline solid. LC/MS 452.5 (M+1).

Step D:tert-Butyl[(3R,4R)-1-(2,3-dimethyl-3H-imidazo[4,5-b]pyridine-5-yl)-4-(2,4,5-trifluorophenyl)piperidin-3-yl]carbamate

A solution of 114 mg (0.25 mmol) of the product of Step C in 5 mL of 1:1trimethyl orthoacetate/toluene was heated at reflux under nitrogen for24 h. The solution was cooled to ambient temperature then evaporated invacuo and the crude oil was carried forward without furtherpurification.

Step E:(3R,4R)-1-(2,3-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl)-4-(2,4,5-trifluorophenyl)piperidin-3-aminebis-trifluoroacetic acid salt

The crude product from Step D was dissolved in 5 mL of 1:1dichloromethane/trifluoroacetic acid and stirred at ambient temperaturefor 60 min. The solution was then concentrated to yield a viscous crudeoil which was purified by reverse phase HPLC (YMC Pro-C18 column,gradient elution, 0 to 80% acetonitrile/water with 0.1% TFA) to affordthe title compound as a white crystalline solid. LC/MS 376.2 (M+1).

Following essentially the procedures outlined for Examples 1-6, theExamples listed in Table 1 were prepared.

TABLE 1

Example R¹ MS (M + 1) 7

308.3 8

308.4 9

308.4 10

309.3 11

309.3 12

309.3 13

342.3 14

338.1 15

376.3 16

376.3 17

353.3 18

333.4 19

376.4 20

376.2 21

343.2 22

403.2 23

403.3 24

358.2 25

358.4 26

358.3 27

348.4 28

349.4 29

417.4 30

391.2 31

405.4 32

443.2 33

391.4 34

431.4 35

431.4 36

426.3 37

426.5 38

426.5 39

377.5 40

467.2 41

389.2 42

415.1 43

416.4 44

420.3 45

392.2 46

382.1 47

417.2 48

390.2 49

408.0 50

379.2 51

390.2 52

374.1 53

376.2 54

361.1Example of a Pharmaceutical Formulation

As a specific embodiment of an oral pharmaceutical composition, a 100 mgpotency tablet is composed of 100 mg of any of Example 1, 268 mgmicrocrystalline cellulose, 20 mg of croscarmellose sodium, and 4 mg ofmagnesium stearate. The active, microcrystalline cellulose, andcroscarmellose are blended first. The mixture is then lubricated bymagnesium stearate and pressed into tablets.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inresponsiveness of the mammal being treated for any of the indicationswith the compounds of the invention indicated above. The specificpharmacological responses observed may vary according to and dependingupon the particular active compounds selected or whether there arepresent pharmaceutical carriers, as well as the type of formulation andmode of administration employed, and such expected variations ordifferences in the results are contemplated in accordance with theobjects and practices of the present invention. It is intended,therefore, that the invention be defined by the scope of the claimswhich follow and that such claims be interpreted as broadly as isreasonable.

1. A compound of the formula I:

or a pharmaceutically acceptable salt thereof; wherein each n isindependently 0, 1, 2 or 3; Ar is phenyl unsubstituted or substitutedwith one to five R³ substituents; each R³ is independently selected fromthe group consisting of halogen, cyano, hydroxy, C₁₋₆ alkyl,unsubstituted or substituted with one to five halogens, and C₁₋₆ alkoxy,unsubstituted or substituted with one to five halogens; R¹ is heteroarylunsubstituted or substituted with one to four R² substituents, whereinthe heteroaryl is selected from the group consisting of

each R² is independently selected from the group consisting of hydroxy,halogen, cyano, nitro, C₁₋₁₀ alkoxy, wherein alkoxy is unsubstituted orsubstituted with one to five substituents independently selected fromhalogen or hydroxy, C₁₋₁₀ alkyl, wherein alkyl is unsubstituted orsubstituted with one to five substituents independently selected fromhalogen or hydroxy, C₂₋₁₀ alkenyl, wherein alkenyl is unsubstituted orsubstituted with one to five substituents independently selected fromhalogen or hydroxy, (CH₂)_(n)-aryl, wherein aryl is unsubstituted orsubstituted with one to five substituents independently selectedhydroxy, halogen, cyano, nitro, CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkyl,and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five halogens, (CH₂)_(n)-heteroaryl, whereinheteroaryl is unsubstituted or substituted with one to threesubstituents independently selected from hydroxy, halogen, cyano, nitro,CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyland alkoxy are unsubstituted or substituted with one to five halogens,(CH₂)_(n)-heterocyclyl, wherein heterocyclyl is unsubstituted orsubstituted with one to three substituents independently selected fromoxo, hydroxy, halogen, cyano, nitro, CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₆alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five halogens, (CH₂)_(n)—C₃₋₆ cycloalkyl,wherein cycloalkyl is unsubstituted or substituted with one to threesubstituents independently selected from halogen, hydroxy, cyano, nitro,CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyland alkoxy are unsubstituted or substituted with one to five halogens,(CH₂)_(n)—COOH, (CH₂)_(n)—COOC₁₋₆ alkyl, (CH₂)_(n)—NR⁴R⁵,(CH₂)_(n)—CONR⁴R⁵, (CH₂)_(n)—OCONR⁴R⁵, (CH₂)_(n)—SO₂NR⁴R⁵,(CH₂)_(n)—SO₂R⁶, (CH₂)_(n)—NR⁷SO₂R⁶, (CH₂)_(n)—NR⁷CONR⁴R⁵,(CH₂)_(n)—NR⁷COR⁷, and (CH₂)_(n)—NR⁷CO₂R⁶; wherein any individualmethylene (CH₂) carbon atom in (CH₂)_(n) is unsubstituted or substitutedwith one to two groups independently selected from halogen, hydroxy,C₁₋₄ and C₁₋₄ alkoxy, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five halogens; R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen, (CH₂)_(n)-phenyl,(CH₂)_(n)—C₃₋₆ cycloalkyl, and C₁₋₆ alkyl; wherein alkyl isunsubstituted or substituted with one to five substituents independentlyselected from halogen and hydroxy and wherein phenyl and cycloalkyl areunsubstituted or substituted with one to five substituents independentlyselected from halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, whereinalkyl and alkoxy are unsubstituted or substituted with one to fivehalogens; or R⁴ and R⁵ substituents together with the nitrogen atom towhich they are attached form a heterocyclic ring selected fromazetidine, pyrrolidine, piperidine, piperazine, and morpholine whereinsaid heterocyclic ring is unsubstituted or substituted with one to threesubstituents independently selected from halogen, hydroxy, C₁₋₆ alkyl,and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five halogens; each R⁶ is independently C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one to fivesubstituents independently selected from halogen and hydroxyl; and R⁷ ishydrogen or R⁶.
 2. The compound of claim 1 wherein R³ is selected fromthe group consisting of fluorine, chlorine, bromine, methyl,trifluoromethyl, and trifluoromethoxy.
 3. The compound of claim 1wherein said heteroaryl group R¹ is selected from the group consistingof:


4. The compound of claim 3 wherein said heteroaryl group R¹ is selectedfrom the group consisting of:


5. The compound of claim 4 wherein said heteroaryl group R¹ is selectedfrom the group consisting of:


6. The compound of claim 1 wherein R² is selected from the groupconsisting of halogen, cyano, nitro, C₁₋₁₀ alkoxy, wherein alkoxy isunsubstituted or substituted with one to five substituents independentlyselected from halogen or hydroxy, C₁₋₁₀ alkyl, wherein alkyl isunsubstituted or substituted with one to five substituents independentlyselected from halogen or hydroxy, aryl, wherein aryl is unsubstituted orsubstituted with one to five substituents independently selectedhydroxy, halogen, cyano, nitro, CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkyl,and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five halogens, heteroaryl, wherein heteroaryl isunsubstituted or substituted with one to three substituentsindependently selected from hydroxy, halogen, cyano, nitro, CO₂H, C₁₋₆alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxyare unsubstituted or substituted with one to five halogens, and C₃₋₆cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with oneto three substituents independently selected from halogen, hydroxy,cyano, nitro, COOH, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy,wherein said alkyl and alkoxy are unsubstituted or substituted with oneto five halogens.
 7. The compound of claim 6 wherein R² is selected fromthe group consisting of: fluoro, chloro, cyano, nitro, C₁₋₄ alkyl,trifluoromethyl, methoxy, 4-fluorophenyl, cyclohexyl, and thienyl. 8.The compound of claim 1 of structural formulae Ia and Ib having theindicated stereochemical configuration at the two stereogenic piperidinecarbon atoms marked with an *:


9. The compound of claim 8 of structural formula Ia having the indicatedabsolute stereochemical configuration at the two stereogenic piperidinecarbon atoms marked with an *:


10. The compound of claim 9 wherein Ar is phenyl unsubstituted orsubstituted with one to three R³ substituents independently selectedfrom fluorine and trifluoromethyl; and R¹ is a heteroaryl group selectedfrom the group consisting of:

wherein said heteroaryl group is unsubstituted or substituted with oneto two R² substituents independently selected from the group consistingof: fluoro, chloro, cyano, nitro, C₁₋₄ alkyl, trifluoromethyl, methoxy,4-fluorophenyl, cyclohexyl, and thienyl.
 11. The compound of claim 10wherein said heteroaryl group R¹ is selected from the group consistingof:


12. The compound of claim 10 which is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition which comprises a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 14. The pharmaceutical composition of claim 13additionally comprising metformin.
 15. A method for treating non-insulindependent (Type 2) diabetes in a mammal in need thereof which comprisesthe administration to the mammal of a therapeutically effective amountof a compounds of claim 1.